Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans.

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Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

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Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans

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Robin A. McGregor a,b,c,∗ , Sally D. Poppitt a,b,d , David Cameron-Smith c a

School of Biological Sciences, University of Auckland, Auckland, New Zealand Human Nutrition Unit, University of Auckland, Auckland, New Zealand Liggins Institute, University of Auckland, Auckland, New Zealand d Riddet Institute, Palmerston North, New Zealand b c

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Article history: Received 19 November 2013 Received in revised form 1 May 2014 Accepted 5 May 2014 Available online xxx

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Keywords: Sarcopenia miRNA 20 Aging 21 Senescence 22 23 Q2 Stem cell Exercise 24 Diet 25 Muscle 26 18 19

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Progressive age-related changes in skeletal muscle mass and composition, underpin decreases in muscle function, which can inturn lead to impaired mobility and quality of life in older adults. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in skeletal muscle and are associated with aging. Accumulating evidence suggests that miRNAs play an important role in the agerelated changes in skeletal muscle mass, composition and function. At the cellular level, miRNAs have been demonstrated to regulate muscle cell proliferation and differentiation. Furthermore, miRNAs are involved in the transitioning of muscle stem cells from a quiescent, to either an activated or senescence state. Evidence from animal and human studies has shown miRNAs are modulated in muscle atrophy and hypertrophy. In addition, miRNAs have been implicated in changes in muscle fiber composition, fat infiltration and insulin resistance. Both exercise and dietary interventions can combat age-related changes in muscle mass, composition and function, which may be mediated by miRNA modulation in skeletal muscle. Circulating miRNA species derived from myogenic cell populations represent potential biomarkers of aging muscle and the molecular responses to exercise or diet interventions, but larger validation studies are required. In future therapeutic approaches targeting miRNAs, either through exercise, diet or drugs may be able to slow down or prevent the age-related changes in skeletal muscle mass, composition, function, hence help maintain mobility and quality of life in old age. © 2014 Published by Elsevier B.V.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNA discovery, biogenesis, processing and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNA regulation in aging human muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNAs in muscle stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNAs in skeletal muscle cell differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNAs and skeletal muscle cell senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNAs and muscle atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MiRNAs, muscle composition, fat infiltration and insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muscle miRNA modulation by exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Muscle miRNAs and resistance exercise training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Muscle miRNAs and aerobic exercise training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Circulating miRNAs as biomarkers of skeletal muscle function and adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. MiRNAs modulated by diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1001, New Zealand. Tel.: +64 96301162; fax: +64 96305764. E-mail address: [email protected] (R.A. McGregor). http://dx.doi.org/10.1016/j.arr.2014.05.001 1568-1637/© 2014 Published by Elsevier B.V.

Please cite this article in press as: McGregor, R.A., et al., Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans. Ageing Res. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2014.05.001

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Aging is associated with progressive changes in skeletal muscle mass and composition, underpinning a decline in muscle function, which in turn has a major impact on mobility and quality of life (Cruz-Jentoft et al., 2010). Skeletal muscle tissue makes up ∼40% of body weight in healthy humans, and is essential for locomotion and metabolic homeostasis. The age-related loss of skeletal muscle mass occurs slowly over several decades, with muscle loss estimated at 1–2% per year from the fifth decade onwards. Age-related changes in muscle composition and metabolism also underpin muscle function, and may proceed the loss of muscle mass in some individuals (Goodpaster et al., 2006). The progressive changes in skeletal muscle observed with age are influenced by an interaction of intrinsic aging processes and environmental factors. Intrinsic factors which can impact muscle mass, composition and function during human aging include DNA damage, insulin resistance, low-grade inflammation, cellular stress, mitochondrial dysfunction, cellular senescence and stem cell exhaustion (López-Otín et al., 2013). Environmental factors which can influence muscle mass, composition and function during human aging include physical inactivity (Evans, 2010), nutrient availability (Paddon-Jones et al., 2008), impaired metabolism (McGregor and Poppitt, 2013) and comorbidity (Dimmeler and Nicotera, 2013). Studies to delineate the relative contribution of intrinsic or environmental factors to the changes in human muscle tissue with age are hampered by the length of the average human lifespan. Many of the hallmarks underpinning intrinsic aging can be modulated by environmental factors and thus contribute to changes in muscle mass, composition and function with age. Overall human lifespan and changes in muscle and other tissues with age are proposed to be initially genetically determined, but environmental factors in early, mid and late life may slow down or accelerate the deterioration of tissue. A major current challenge is identifying common regulatory mechanisms, that underpin changes in skeletal muscle mass, composition and function during aging, which inturn can provide early biomarkers for mid-life screening and timely interventions to promote healthy aging such as exercise or diet. Over the past decade miRNAs have been established as important regulators of multiple biological processes underpinning cell development, growth and death (Alvarez-Garcia and Miska, 2005). MiRNAs have been identified which govern skeletal muscle proliferation, differentiation and apoptosis at the cellular level (Wang, 2013). Evidence is also growing that miRNAs play a role in governing cell senescence (Cheung et al., 2012; Smith-Vikos and Slack, 2012), although it is not understood when senescence of muscle stem cells commences in life and how senescence contributes to changes in muscle mass, composition and function. In animal models of skeletal muscle atrophy (Kukreti et al., 2013) and hypertrophy (Chaillou et al., 2013) miRNAs appear to be dynamically regulated. Furthermore, clinical studies examining miRNA expression in elderly humans demonstrate that miRNAs may play a role in the age-related changes in skeletal muscle phenotype (Drummond et al., 2011, 2008; Olivieri et al., 2012). In this review, we discuss the role of miRNAs in muscle aging primarily from a human perspective. We provide an overview of miRNAs that regulate muscle proliferation, differentiation and senescence at the cellular level. We go on to discuss the evidence that miRNA plays an important role in the age-related changes in skeletal muscle mass, composition and function. We highlight the potential of miRNAs

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as biomarkers of muscle function during mid-life and later-life. Finally, we discuss emerging evidence that exercise and diet modulate miRNA expression, therefore may partly explain the beneficial effect of these interventions on skeletal muscle mass, composition and function. 2. MiRNA discovery, biogenesis, processing and function Over a decade ago, small non-coding miRNAs were discovered in Caenorhabditis elegans and homologues were identified in vertebrates and humans (Lagos-Quintana et al., 2001). MiRNAs regulate the expression of partially complementary mRNAs (Bartel, 2009). MiRNAs are mainly encoded within intronic and intergenic regions of the genome. The most recent deep-sequencing efforts indicate the human genome contains over 1500 miRNA genes (Kozomara and Griffiths-Jones, 2011). MiRNAs are expressed in developmental, cell-type and tissue specific patterns (Sood et al., 2006). This specificity extends to skeletal muscle where specific miRNAs are preferentially expressed in myoblasts and myotubes (Chen et al., 2006). Skeletal muscle is characterized by high tissuespecific expression of miR-1, miR-206 and miR-133, which have been termed myomiRs (Sood et al., 2006), although several hundred miRNAs are detectable in skeletal muscle. MiRNAs are initially transcribed as longer primary miRNA transcripts >500 nt and later cleaved by Drosha, an RNase III enzyme in the nucleus, resulting in shorter ∼70 nt precursor miRNAs as illustrated in Fig. 1 (Lee et al., 2003). Pre-miRNAs are exported from the nucleus via the nuclear transport protein Exportin5 (Lund et al., 2004). In the cytoplasm, pre-miRNAs are cleaved by the enzyme Dicer, resulting in miRNA duplexes which harbor the mature miRNA strand (Kim et al., 2009). Functional mature miRNAs are then loaded into an RNA induced silencing complex

Fig. 1. MicroRNA (miRNA) biogenesis pathway. MicroRNAs are transcribed as long primary miRNA (pri-miRNAs) transcripts, then cleaved by Drosha to form shorter precursor miRNAs (pre-miRNAs) in the nucleus. Pre-miRNAs are exported to the cytoplasm via Exportin5, then cleaved by Dicer to form miRNA duplexes which unwind. Mature miRNAs are loaded in RNA induced silencing (RISC) complexes containing Argonaute and bind to the complementary 3 UTRs of target genes leading to post-transcriptional suppression.


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(RISC) containing Argonaute (see Fig. 1). Mature miRNAs primarily regulate targets by binding to complementary sites within the 3 UTR region of protein coding genes (Bartel, 2009), which in turn leads to translational repression, mRNA deadenylation and decay (Djuranovic et al., 2012). Each individual miRNA can bind to several hundred target genes which harbor complementary bindings sites within the 3 UTR region (Bartel, 2009), hence miRNAs act as powerful post-transcriptionally regulators of gene expression and protein levels (Bartel, 2009). Over 45,000 putative miRNA target sites have now been identified in human 3 UTRs (Friedman et al., 2009). Microarray profiling studies provided the first evidence that miRNAs regulate the expression of hundreds of target mRNAs (Lim et al., 2005). Subsequent global proteomics profiling of mouse neutrophils after in vivo deletion of miR-223 revealed compelling evidence that miRNAs fine-tune the abundance of proteins through translational repression of complementary targets (Baek et al., 2008). Overexpression or knockdown of endogenous miRNAs in cells provided further evidence that individual miRNAs regulate the synthesis of several thousand proteins (Selbach et al., 2008). While miRNAs are predicted to regulate a wide-range of target genes post-transcriptionally and hence modulate protein abundance, many miRNA targets still remain to be experimentally validated (Bartel, 2009). Nevertheless, evidence is growing that miRNAs play a role in the age related changes in skeletal muscle (Smith-Vikos and Slack, 2012) and skeletal muscle function (Güller and Russell, 2010).

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3. MiRNA regulation in aging human muscle

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Genetic studies have shown that miRNAs regulate longevity in C. elegans, subsequently numerous miRNAs have been shown to be up or down-regulated with chronological age (de Lencastre et al., 2010; Grillari and Grillari-Voglauer, 2010). Multiple miRNA targets have been identified in conserved signaling pathways that govern longevity in C. elegans. For example, DAF-2 which functions as an insulin receptor and DAF-16 which is a fork head box (FOXO) transcription factor are targeted by lin-14 and lin-4 respectively. DAF-16 transcriptionally activates or represses genes governing cellular stress and longevity (Smith-Vikos and Slack, 2012), although an important caveat is that DAF-16 is primarily expressed in neurons and the small intestine, rather than muscle. To date there have been no longitudinal studies of miRNA changes with age in human skeletal muscle (Kato and Slack, 2013). Therefore, evidence of miRNA regulation in aging mammalian muscle is based on observations of differential miRNA expression in young and old animals (Hamrick et al., 2010; Mercken et al., 2013). In quadriceps muscle of old (24 month) mice, miR-206, miR-7, miR-542, miR-468 and miR-698 were reported to be upregulated, while miR-181a, miR-434, miR-382, miR-455, miR-124a and miR221 were downregulated compared to young (12 month) mice (Hamrick et al., 2010). Whereas in old rhesus monkeys, miR-451, miR-144, miR-18a and miR-15a were found to be upregulated in skeletal muscle, while miR-181a/b was reported to be downregulated compared to young controls (Mercken et al., 2013). While these mammalian models share some characteristics of human aging such as loss of muscle mass, miRNA expression appears to vary between models (Hamrick et al., 2010; Mercken et al., 2013). Studies in C. elegans indicate the majority of miRNAs are downregulated with age (de Lencastre et al., 2010), whereas studies in mice indicate a broad upregulation of miRNA expression with age in different tissues (Li et al., 2011b), it will also be important in future to establish the timecourse of changes in miRNA expression in human skeletal muscle. Several primary miRNA transcripts which are precursors of mature muscle specific miRNAs were reported to be upregulated in elderly muscle, including pri-miR-1-1, pri-miR-1-2,

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pri-miR-133a-1 and pri-miR-133a-2, although there was no difference in mature miR-1, miR-133 or miR-206 expression compared to younger muscle (Drummond et al., 2008). Microarray profiling of miRNAs in skeletal muscle biopsies from young and old adults revealed eighteen candidate miRNAs either up- or down-regulated (Drummond et al., 2011). In the latter study, the older individuals tended to have lower lean muscle mass than the young controls. Let-7b and let-7e were consistently upregulated in the older adults based on miRNA array and RT-qPCR analysis. The let-7 family is predicted to target cell cycle genes several of which were suppressed in the older adults including CDK6, CDC25A and CDC34. The inconsistency between aged-related muscle miRNA expression in humans and mammalian models may be partly attributable to the greater influence of environmental factors in human muscle aging studies compared to laboratory-raised animals. To delineate the relative contribution of environmental factors to muscle miRNA expression in old age it would be useful to analyze muscle biopsies from young and old subjects with varying physical activity levels and dietary intake, which are known to influence muscle mass, composition and function. In addition, while each miRNA is predicted to target hundreds of genes for post-transcriptional regulation, further experimental validation is essential to confirm targets of the aging related miRNAs identified in human skeletal muscle so far.

4. MiRNAs in muscle stem cells Age-related changes in muscle mass, composition and function are underpinned by changes at the cellular level. Muscle satellite cells are myogenic progenitor cells responsible, in part, for skeletal muscle renewal, regeneration and adaptation (Hawke and Garry, 2001). The muscle satellite cell population is reported to decline with age in mice (Shefer et al., 2006) and satellite cell content is reduced in type II muscle fibers in the elderly (Verdijk et al., 2007). Furthermore, in older men the expansion of muscle satellite cells populations during recovery from immobility-induced atrophy is suppressed (Suetta et al., 2013). The skeletal muscle satellite cell population is closely regulated by myogenic transcription factors and a subset of miRNAs, which control genes governing proliferation and differentiation. During satellite cell differentiation, the largest changes occur in the muscle-specific miRNAs including miR-1, miR-133a, miR-206 and miR-499 (Chen et al., 2011). One specific example of this relationship between myogenic regulator genes and a miRNA was demonstrated recently for Pax3 which harbors a miR-206 binding site in its 3 UTR region (Boutet et al., 2012). Pax3 is transiently expressed during the activation of muscle stem cells and regulates the entry of muscle satellite cells into the myogenic program. Elevated miR-206 levels normally inhibits Pax3 expression in quiescent satellite cells and activated satellite cells, but in a subset of quiescent stem cells miR-206 and Pax3 are coexpressed at high levels, which is possible due to alternate polyadenylation and shortening of the 3 UTR of Pax3 in this subset of cells (Boutet et al., 2012). During myogenesis, a fraction of muscle satellite cells re-enter quiescence rather than undergoing differentiation into multinucleated myotubes. The maintenance of a pool of quiescence satellite cells is important for future muscle regeneration. When proliferating satellite cells enter quiescence, miRNAs are globally downregulated, with miR-106b, miR-25, miR-29c and miR-320c abundance significantly reduced (Koning et al., 2012). Recent microarray analysis of satellite-cells from adult mice identified miRNA-489 as a quiescence-specific miRNA (Cheung et al., 2012). Functional studies revealed miR-489 can post-transcriptionally suppress Dek, an oncogene which normally localizes from satellite cells to differentiated daughter cells during asymmetric division (Cheung et al., 2012). Whether miR489 is a biomarker of muscle satellite cell lineage in adult humans


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is not yet clear, as small biopsies that consist of a mixture of cell types are used for the analysis of miRNA expression in human skeletal muscle. The potential to manipulate miRNAs involved in muscle satellite cell quiescence could allow the regenerative capacity of skeletal muscle to be restored or maintained during aging in future. 5. MiRNAs in skeletal muscle cell differentiation Skeletal muscle cell proliferation and differentiation underpin increases in muscle mass and skeletal muscle remodeling. Overexpression of miR-1 and miR-206 accelerates differentiation, while overexpression of miR-133 stimulates proliferation of murine myoblasts (Chen et al., 2006). The myogenic transcription factor MEF2 is activated during skeletal muscle differentiation and can bind to the bicistronic primary transcript, which encodes miR-1 and miR-133a-1. Mature miR-1 can also bind to the 3 UTR of MEF2, hence forming a negative feedback loop to reduce primary transcript levels (Liu et al., 2007). Inhibition of miR-1 and miR-206 during differentiation of myoblasts into myotubes blocks suppression of many targets required for muscle differentiation (Goljanek-Whysall et al., 2012). Besides the muscle-specific miRNAs, other miRNAs are now being identified which can modulate myogenesis. Recently, miR-128a was demonstrated to inhibit myoblast cell proliferation and promote differentiation via targeting insulin signaling genes including Insr, Irs1 and Pik3r1 (Motohashi et al., 2013). Most studies to date of miRNA involvement in myogenic differentiation have been performed in vitro. However, a recent in vivo study demonstrated miR-26a can promote differentiation by targeting the transcription factors Smad1 and Smad4, which are key players in the TGF-␤/BMP pathway (Dey et al., 2012). Injection of neonatal mice with antagomirs or adenovirus against miR-26a resulted in increased Smad expression and activity, which in turn suppressed skeletal muscle differentiation (Dey et al., 2012). In addition, direct modulation of muscle specific miRNAs after muscle injury can accelerate or inhibit muscle regeneration following tissue injury (Liu et al., 2012; Nakasa et al., 2010). Injection of double-stranded miR-1, miR-133 and miR-206 into lacerated tibialis anterior, resulted in enhanced muscle regeneration after 1 week, which was associated with increased PAX7, MyoD and myogenin expression (Nakasa et al., 2010). Conversely, in mice lacking miR-206, muscle regeneration following injury is impaired (Liu et al., 2012). Taken together, evidence from in vitro cell studies demonstrate miRNAs play a crucial role in skeletal muscle differentiation and direct in vivo modulation of miRNA levels can inhibit or promote muscle differentiation or regeneration. 6. MiRNAs and skeletal muscle cell senescence Cellular senescence causes stable cell cycle arrest and is a hallmark of aging. Senescence can be triggered by a variety of factors including telomere shortening, DNA damage and cellular stress (López-Otín et al., 2013). MiRNAs have been implicated in the senescence of multiple mammalian cell types during aging (Hackl et al., 2010). Recently, the clearance of p16Ink4a -positive senescence cells in late-life, which are found in a variety of tissues including skeletal muscle and adipose tissue was shown to slow the progression of age-related disorders (Baker et al., 2011). MiRNAs regulate the cellular senescence program by targeting genes involved in cellular stress and tumor suppressor pathways. Numerous miRNAs can bind to targets in the tumor suppressor pathways p53 and Rb, such as miR-29 and miR-30 which have been shown to inhibit Rb-dependent senescence (Martinez et al., 2011). In addition, senescence cells secrete proinflammatory cytokines which may contribute to the chronic low-grade systemic inflammation associated with aging (Rodier et al., 2009). Inflammatory

mediators interleukin-6 and interleukin-8 are targets of miR-146a and b which appears to be part of a compensatory response to protect against inflammation in senescent primary fibroblasts (Bhaumik et al., 2009). At least some of the miRNA changes in senescence cells appear to be part of a protective response to prevent damaged cells from proliferating. However, the time-course of the development and accumulation of senescence muscle stem cells with age in humans is unknown. It may be speculated that cell senescence primarily occurs later in life, and may contribute to the accelerated decline in skeletal muscle function in the elderly and frail. Nevertheless further studies are needed to investigate whether muscle stem cell senescence associated miRNAs are altered during middle-age. 7. MiRNAs and muscle atrophy Progressive loss of muscle mass occurs with age, with estimates of 1–2% per year from the fifth decade onwards in older adults. Given the slow rate of change, the role of miRNAs in age-related loss of skeletal muscle has been assessed in a variety of experimental animal models exhibiting skeletal muscle atrophy. These studies indicate that a common muscle atrophy program may underlie wasting as present in multiple experimental models (Lecker et al., 2004). Despite the established role of muscle specific miRNAs in differentiation, varying miRNA expression patterns have been observed in animal muscle atrophy models such as space flight, muscular dystrophy, hindlimb suspension, dexamethasone mediated and hindlimb ischemia. Expression of miR-206 was observed to be downregulated in unloaded skeletal muscle following space flight (Allen et al., 2009). MDX mice which are commonly used as a model of Duchenne muscular dystrophy (DMD) are characterized by muscle atrophy which is driven by a genetic mutation of the dystrophin gene that results in the development of muscle necrosis and weakness at a young age. MDX mice were reported to have higher miR-206 expression in the diaphragm muscle, but not in the hindlimb muscle (McCarthy et al., 2007). Another study of MDX mice reported miR-206 was higher in the tiabialis anterior muscle, although no differences in the other muscle-specific miRNAs were found (Yuasa et al., 2008). In addition, a global miRNA array study in the MDX mice revealed miR-31 and miR-34x clusters were upregulated, including primary-miRNA transcripts, pre-miRNA transcripts and mature miRNAs (Roberts et al., 2012). Furthermore, musclespecific miR-1, miR-133a and miR-206 were found to be highly abundant in serum of mdx mice, but were either downregulated or modestly upregulated in skeletal muscle (Roberts et al., 2012). Hindlimb suspension is also used as a model of muscle atrophy. During 28 days of hindlimb suppression in mice, miR-499 and miR-208b were among several miRNAs observed to be downregulated in soleus muscle (McCarthy et al., 2009). The changes in miR-499 and miR-208b expression were consistent with repression of a network of beta-myosin heavy chain (MHC-␤) gene expression (McCarthy et al., 2009). MHC-␤ is a contractile protein expressed predominantly expressed in Type I skeletal muscle fibers, therefore is important for muscle function. The varying miRNA expression observed in different muscle atrophy models suggests that modulation of muscle miRNAs such as miR-206 maybe indicative of muscle remodeling. There is also evidence of miRNA regulation of the ubiquitin ligase pathway, which plays a role in protein degradation. MAFbx/atrogin-1 and MuRF1 are both involved in the ubiquitin ligase pathway associated with muscle atrophy. Both MAFbx and MuRF1 harbor binding sites within their 3 UTRs, which are complementary to miR-23a. Transgenic miR-23 mice were reported to be resistant to dexamethasone mediated muscle atrophy (Wada et al., 2011). Fast-twitch fibers are preferentially lost in dexamethasone mediated muscle atrophy, but were found


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to be preserved in transgenic miR-23 mice (Wada et al., 2011). Hindlimb ischemia is a well established model which leads to hypoxia-induced apoptosis in both endothelial and skeletal muscle cells. A recent study using comparative miRNA profiling of inbred mouse strains with varying recovery rates after hindlimb ischemia, revealed muscle miR-93 attenuated apoptosis and enhanced proliferation (Hazarika et al., 2013). The variability in muscle specific miRNA expression changes in different muscle atrophy models suggest modulation of miRNAs in muscle may be a biomarker of muscle remodeling, alternatively differences in the proportion of quiescent, proliferating muscle cells, differentiated muscle cells, adipogenic cells, fibrotic cells and inflammatory cells may influence miRNA expression in muscle tissues. In addition, mouse muscle atrophy models are characterized by accelerated muscle wasting, whereas age-related muscle wasting occurs slowly over many years. Moving forwards, assessing miRNA expression and their targets at multiple timepoints during the development of muscle atrophy will provide a clearer picture of miRNAs which may be involved in the age-related loss of muscle mass. Clinical studies of accelerated muscle wasting due to muscular dystrophies, sepsis, COPD and following bed-rest have also reported altered levels of miRNA expression (Eisenberg et al., 2007; Fredriksson et al., 2008; Lewis et al., 2012; Ringholm et al., 2011). MiRNA profiling of human skeletal muscle from patients with a range of primary muscular disorders revealed five miRNAs were commonly dysregulated, including miR-146b, miR-155, miR-214 and miR-222 (Eisenberg et al., 2007). In ICU patients, rapid muscle atrophy occurs which can prolong recovery due to bed-rest and systemic inflammation. Inflammatory associated miR-21, along with its precursor transcript was reported to be elevated in skeletal muscle of ICU patients (Fredriksson et al., 2008). MiR-21 is predicted to target genes involved in the ubiquitin-proteolysis pathway. Muscle atrophy also occurs in patients with chronic obstructive pulmonary disease (COPD). Expression of miR-1 was found to be reduced in COPD patients and correlated with fat-free mass and muscle function tests (Lewis et al., 2012). Furthermore, expression of miR-133 and miR-206 abundance was reported to be negatively correlated with physical activity (Lewis et al., 2012). Prolonged, bed rest also induces progressive muscle atrophy and decreases in mitochondria number. A study in healthy young men after seven days of bed rest showed mitochondrial DNA and oxidation phosphorylation enzymes were reduced, as well as miR-1 and miR-133a abundance (Ringholm et al., 2011). Taken together these studies demonstrate miRNA expression is modulated during muscle atrophy in humans under a variety of conditions. It will be important in future to establish whether miRNA expression is associated with varying degrees of age-related muscle loss in the middle-age and old age. However, muscle mass is not the sole determinant of age-related changes in muscle strength, physical function and mobility (Goodpaster et al., 2006). Recent evidence points to shifts in muscle fiber type, intramuscular lipid infiltration and other factors which influence muscle composition, and hence underpin muscle function in older adults.

8. MiRNAs, muscle composition, fat infiltration and insulin resistance Age-related muscle loss primarily affects the type II fibers with relative maintenance of the type I fiber population (Evans and Lexell, 1995). Type I fibers are adapted to generate energy primarily via oxidative phosphorylation and contraction time is slower, whereas type II fibers are adapted to generate energy primarily from non-oxidative sources and contraction time is faster. MiRNA expression profiles differ between fiber types (Liu et al., 2012). Furthermore, a recent study has revealed a distinct miRNA network which regulates the development of type I fibers (Gan et al., 2013).

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MiR-499 and miR-208b facilitate the development of type I muscle fibers via estrogen-related receptor gamma (ESRRG) activation (Gan et al., 2013). Skeletal muscle from endurance exercise trained individuals, characterized by a higher proportion of Type I muscle fibers, have greater miR-499 and ESRRG expression than sedentary individuals (Gan et al., 2013). To date there have been no studies which have examined miRNA expression in different muscle fiber types in younger or older adults. Adipocyte infiltration into skeletal muscle is a characteristic of aging muscle (Delmonico et al., 2009). Build up of fat and connective tissue may contribute to impaired muscle function and decline in mobility with age (Beavers et al., 2013). The origin of these intramuscular adipocytes and fibroblasts are not well understood. Human skeletal muscle-derived progenitor cells have been demonstrated to have both adipogenic (Vettor et al., 2009) and osteogenic differentiation capacity (Oishi et al., 2013). Fibroblastlike preadipocytes cultured from bovine muscle tissue are reported to be capable of differentiation into mature adipocytes characterized by up-regulation of miR-143 (H. Li et al., 2011a). Whether aging is associated with altered stem cell fate is not well established, and the increased levels in intramuscular lipids and fibrotic cells may be partly due to high dietary fat intake, as miRNAs in skeletal muscle are regulated in response to a high-fat diet (Chen et al., 2012). The development of insulin resistance is another wellestablished hallmark of aging (López-Otín et al., 2013). Skeletal muscle is a major site of insulin stimulated glucose uptake in the post-prandial state, therefore loss of muscle mass can lead to increased insulin resistance. MiRNAs have been implicated in regulating insulin sensitivity and metabolism in animal models of obesity and Type 2 diabetes (Rottiers and Näär, 2012). For example, silencing miR-103 and miR-107 in diet-induced obese mice improves glucose homeostasis and insulin sensitivity, conversely increasing miR-103 and miR-107 impairs glucose homeostasis (Trajkovski et al., 2011). MiR-103/107 have been demonstrated to directly target caveolin-1, which regulates the insulin receptor and insulin signaling (Trajkovski et al., 2011). Let-7 and the RNA-binding protein Lin28 have also been shown to modulate insulin resistance and glucose tolerance (Zhu et al., 2011). Let7 can bind multiple targets in the insulin-PI3K-mTOR pathway such as IGF-1, INSR and IRS2, while Lin28 inhibits Let-7 biogenesis. Either loss of Lin28a or overexpression of let-7 in skeletal muscle leads to the development of insulin resistance, which inturn results in impaired glucose tolerance (Zhu et al., 2011). Let-7 is also reported to be increased in skeletal muscle from Type 2 diabetes patients (Jiang et al., 2013). Another human study including patients with normal glucose tolerance, impaired glucose tolerance or Type 2 diabetes reported muscle-specific miR-133a and miR-206 were downregulated and insulin resistance was inversely correlated with miR-133a expression (Gallagher et al., 2010). Furthermore, changes in circulating miRNAs have been reported over several years in association with changes in fat mass and insulin resistance in children (Prats-Puig et al., 2013). Taken together, these studies provide evidence that miRNAs play a role in insulin resistance and dysregulated metabolism, but whether these miRNAs underpin the development of age-related insulin resistance remains to be established.

9. Muscle miRNA modulation by exercise Habitual physical activity is an important factor contributing to muscle mass and function regardless of age, and exercise is a well-studied intervention for the prevention of the age-related loss of muscle mass and muscle function. Resistance type exercise, which involves progressive overload of muscle, can increase muscle mass in middle-aged and elderly individuals. Endurance


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type exercise which involves prolonged low to moderate intensity activity, can promote a number of positive adaptations in skeletal muscle including increased mitochondria abundance and aerobic capacity. Both types of exercise promote positive adaptations in skeletal muscle, which underpin improvements in muscle strength and endurance, thus help promote healthy aging. MiRNAs have been shown to be involved in the response of skeletal muscle to exercise in both animal models and humans.

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Resistance exercise training is recommended in the middleaged and elderly to promote gains or maintenance of skeletal muscle mass. In a murine study, muscle-specific miR-1 and miR133a were reported to be down-regulation after one week of resistance type training (McCarthy et al., 2007). Expression of the corresponding miRNA precursor transcripts and miRNA processing proteins Drosha and Exportin5 were found to be elevated (McCarthy et al., 2007). In humans differential miRNA expression was recently reported in high compared to low responders to resistance training (Davidsen et al., 2011). In the low responders, miR-378, miR-29a and miR-26a were downregulated and miR-451 was upregulated, while 15 other highly expressed miRNAs were unaltered by resistance training. Collectively, these miRNAs may modulate targets within the mTOR signaling pathway, which is activated during muscle protein anabolism in response to amino acids and resistance exercise (Davidsen et al., 2011). In elderly men and women, miR1 was reported to be downregulated following either 12 weeks of resistance type or eccentric type exercise training, alongside a parallel increase in expression of IGF-1 which promotes muscle growth (Mueller et al., 2011). Although, each exercise modality leads to distinct molecular and structural adaptations in muscle (Mueller et al., 2011), the change in miR-1 may reflect muscle remodeling as only resistance exercise increased muscle cross-sectional area.

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Aerobic exercise training also causes significant changes in muscle metabolism, resulting in enhanced capacity for physical work. In mice, aerobic exercise training has been shown to upregulate miR181, miR-1 as well as miR-107, and downregulate miR-23 (Safdar et al., 2009). PGC-1␣ which regulates mitochondrial biogenesis contains putative binding sites for miR-23a, therefore downregulation of miR-23a reduce inhibition PGC-1␣ (Safdar et al., 2009). In humans, an acute bout of exercise was reported to increase miR-1 and miR-133 in skeletal muscle before but not after training (Nielsen et al., 2010). In addition, basal expression of miR-1, miR-133a, miR-133b and miR-206 was reported to be suppressed by 12 weeks aerobic exercise training, but reverted to pre-training levels within 14 days of training cessation (Nielsen et al., 2010). Predicted target proteins (CDC42 and ERK 1/2) of these musclespecific miRNAs were not found to be consistently inversely related to miRNA expression, hence although miRNAs in muscle respond to physiological stimuli, there role in muscle adaptation to endurance training in humans is not well understood (Nielsen et al., 2010). 10. Circulating miRNAs as biomarkers of skeletal muscle function and adaptation The identification of circulating miRNAs biomarkers of muscle recovery, remodeling and adaptation to exercise training, may facilitate monitoring exercise interventions in middle-aged and older adults to maintain healthy muscle. The origin and function of circulating miRNAs is still not fully understood. After pre-miRNA processing, mature miRNAs can be incorporated into exosomes, microvesicles, apoptosis bodies or bound to RNA-binding proteins

which subsequently can be trafficked to the cell membrane and released into circulation (Xu et al., 2013). Tissue-specific miRNAs have been hypothesized to be released or leak into circulation following stress, injury or tissue damage. Alternatively, miRNAs may undergo active trafficking between cells and play a role in intracellular communication but this remains to be demonstrated in vivo (Xu et al., 2013). Intriguingly, myoblasts and myotubes have been shown to release a repertoire of miRNAs during myogenesis (Forterre et al., 2014). Time-dependent changes in circulating miRNAs have been observed over several hours during recovery from exercise (Baggish et al., 2014). Plasma miR-133 levels were reported to be increased during recovery after eccentric resistance training and marathon running, but were unchanged following a maximal exercise test or prolonged bicycling (Uhlemann et al., 2014). In contrast, another human study observed circulating levels of miR-1, miR-133a, miR-133b and miR-208b were increased between 2 and 6 h after muscle damaging eccentric exercise compared to concentric exercise (Banzet et al., 2013). Many tissues show exercise-induced changes including adipose, liver, heart, lung, endothelium, bone and hence may release miRNAs into circulation. Human studies of circulating miRNAs in response to exercise have not concomitantly assessed the abundance of miRNAs in blood and muscle, therefore it is unknown whether changes in circulating miRNAs during exercise directly reflect changes in muscle miRNA expression. However, the distinct increase in circulating musclespecific miR-133 following eccentric exercise, which is known to cause significant muscle damage, supports the view that miRNAs may be released or secreted from damaged muscle during the recovery. There appears to be discordance between circulating miRNA changes following acute exercise and after chronic exercise training. For example, miR-146a and miR-222 were reported to be upregulated by exercise both before and after chronic exercise training, miR-21 and miR-221 were responsive to exercise only before training, miR-20a was only responsive to chronic exercise training (Baggish et al., 2011). Another recent report of muscleenriched circulating miRNAs in humans after acute and chronic aerobic exercise indicated circulating miR-486 was decreased. The other muscle-enriched miRNAs assessed (miR-1, miR-133a, miR133b, miR-206, miR-208b and miR-499) were detected at low copy numbers in serum (Aoi et al., 2013). Notably in this latter study, miR-486 was reported to be negatively correlated with VO2 max, a measure of aerobic capacity. From a clinical perspective, the identification of circulating miRNA biomarkers which are robust predictors of VO2 max, muscle strength or function may provide a way to rapidly screen for poor muscle function during middle-age using a blood test. Recently, miRNAs have been reported to be associated with aerobic capacity (Bye et al., 2013; Mooren et al., 2014), muscle mass and muscle strength (Donaldson et al., 2013). However, it has been suggested that the prominent source of circulating miRNAs may well be blood cells, as a recent comparison of putative miRNA biomarkers of solid tumors based on screening studies, indicated over fifty percent are highly expressed in blood cells (Pritchard et al., 2012). Changes in blood cell counts and hemolysis can result in up to 50-fold differences in circulating miRNAs detectable in plasma (Pritchard et al., 2012). Therefore, further studies are necessary to determine the origin and function of circulating miRNAs before they can be utilized in the clinic to screen for muscle health and function in older adults.

11. MiRNAs modulated by diet Dietary intake is also an important factor in the loss of muscle mass during aging, low protein intake in the elderly is often associated with increased risk of sarcopenia. There is growing evidence that miRNAs are modulated in response to dietary intake. A recent


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study revealed caloric restriction in rhesus monkeys lead to suppression of age related miR-451 and miR-144 expression in skeletal muscle, and conversely increased miR-181b expression (Mercken et al., 2013). Caloric restriction has long been suggested as a way to extend longevity, but inadequate caloric intake may overtime lead to a progressive loss of muscle mass. In addition, to daily caloric intake, dietary protein intake must be sufficient to meet daily requirements of whole-body protein metabolism otherwise skeletal muscle protein breakdown may exceed muscle protein synthesis and lean muscle mass will be lost (Paddon-Jones et al., 2008). Essential amino acids and protein rich foods such as dairy, meat and soy stimulate muscle protein synthesis. Given that miRNAs have been shown to regulate the synthesis of thousands of proteins (Baek et al., 2008; Selbach et al., 2008), miRNA regulation by protein intake and other dietary factors may be significant in the coordination of protein synthesis in the post-meal period. To date studies have shown that the administration of just 10 g essential amino acids is capable of eliciting increased expression of mature miR-1, -23a, -208b, -499 and pri-miR-206 in skeletal muscle within 3 h of ingestion (Drummond et al., 2009). It is unknown whether increases in dietary protein intake cause acute or chronic changes in miRNA expression muscle. Observations from high-fat diet fed mice suggest the composition of the diet modulates miRNA expression in multiple tissues including subcutaneous and visceral fat (McGregor and Choi, 2011) as well as skeletal muscle (Chen et al., 2012) and other tissues. There is also now evidence that polyphenols and other natural compounds in the diet modulate miRNA expression (Milenkovic et al., 2013). Resveratrol was shown recently to promote skeletal muscle differentiation in part by mediating miRNA expression (Kaminski et al., 2012). Resveratrol is a polyphenol found in grapes which is also reported to improve glycemic control and dyslipidemia (Do et al., 2012). It has been suggested that resveratrol may induce some of its pleotropic effects via modulation of miRNAs that regulate metabolism and disease related pathways (Lançon et al., 2012). Further studies on the impact that acute and chronic dietary interventions, including different types of protein, amino acids or polyphenols, have on the miRNA responses within muscle are required. An emerging hypothesis suggests that exogenous miRNAs also referred to as xenomiRs can be derived directly from the diet and hence may contribute to circulating miRNA levels in blood (Witwer, 2012). This is still a controversial hypothesis and whether dietary derived miRNAs firstly can survive passage through the gastrointestinal tract and secondly can exert functional effects on host physiology remains to be established. Next generation sequencing of plasma miRNAs in humans has shown that a significant fraction of circulating RNA originates from exogenous species such as bacteria, fungi and other organisms (Wang et al., 2012). These findings suggest that some exogenous miRNAs may indeed cross the gut barrier and be released into systemic circulation. Several recent reports indicate human and bovine milk harbors microvesicles which contain miRNAs (Chen et al., 2010; Hata et al., 2010; Izumi et al., 2013). There is a large body of evidence that milk protein may improve metabolic health and has immune-modulatory effects (McGregor and Poppitt, 2013), which potentially may be exerted through miRNAs. High-throughput sequencing of bovine milk, indicates that individual miRNAs are detectable in raw milk, commercial milk and powdered milk products (Chen et al., 2010). Immune-related miRNAs have been reported to be enriched in exosomes derived from breast milk (Zhou et al., 2012), hence may potentially be transferred from the mother’s milk to the infant. Milk-derived microvesicles have been shown to survive acidification conditions which mimic the gastrointestinal tract and appear to be capable of cellular uptake (Hata et al., 2010). Also, recent evidence indicates that milk-derived microvesicles have the ability to transport and deliver miRNAs in to

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cultured macrophages (Sun et al., 2013). The microvesicles appear to be necessary for the cellular uptake of miRNAs by macrophages. While there is accumulating evidence that milk microvesicles are capable of cellular uptake in vitro, it remains to be established whether milk microvesicles or other dietary derived miRNAs can survive the gastrointestinal tract and exert functional effects in vivo.

12. Conclusions Evidence is accumulating that miRNAs play a role in governing skeletal muscle mass, composition and function throughout life. At the cellular level, skeletal muscle miRNAs have been shown to regulate proliferation, differentiation and stem cell populations. MiRNAs are altered by muscle atrophy therefore may play a role in the age related loss of muscle mass. In addition, miRNAs are modulated in metabolic disorders and hence may underpin the development of age-related insulin resistance. Importantly, exercise and dietary changes, which are interventions to combat age-related changes in muscle and help maintain muscle function into old age, have been shown to regulate miRNA expression in skeletal muscle. Circulating miRNAs represent potential noninvasive biomarkers of skeletal muscle remodeling and aging, yet further validation is essential before circulating miRNAs can be used as diagnostic or prognostic biomarkers of age-related changes in muscle mass, composition and function. In future therapeutic approaches targeting miRNAs in muscle either through diet, exercise or drugs may be able to slow down or prevent age-related changes in muscle and thus promote healthy aging.

Acknowledgements RAM and DCS receive financial support from the New Zealand Q3 Primary Growth Partnership (PGP) program, funded by Fonterra Co-operative group and the NZ Ministry for Primary Industries (MPI). SDP holds the Fonterra Chair in Human Nutrition at the University of Auckland.

References Allen, D.L., Bandstra, E.R., Harrison, B.C., Thorng, S., Stodieck, L.S., Kostenuik, P.J., Morony, S., Lacey, D.L., Hammond, T.G., Leinwand, L.L., Argraves, W.S., Bateman, T.A., Barth, J.L., 2009. Effects of spaceflight on murine skeletal muscle gene expression. J. Appl. Physiol. 106, 582–595. Alvarez-Garcia, I., Miska, E.A., 2005. MicroRNA functions in animal development and human disease. Development 132, 4653–4662. Aoi, W., Ichikawa, H., Mune, K., Tanimura, Y., Mizushima, K., Naito, Y., Yoshikawa, T., 2013. Muscle-enriched microRNA miR-486 decreases in circulation in response to exercise in young men. Front. Physiol. 4, 80. Baek, D., Villén, J., Shin, C., Camargo, F.D., Gygi, S.P., Bartel, D.P., 2008. The impact of microRNAs on protein output. Nature 455, 64–71. Baggish, A.L., Hale, A., Weiner, R.B., Lewis, G.D., Systrom, D., Wang, F., Wang, T.J., Chan, S.Y., 2011. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J. Physiol. (Lond.) 589, 3983–3994. Baggish, A.L., Park, J., Min, P.-K., Isaacs, S., Taylor, B.A., Thompson, P.D., Troyanos, C., D’Hemecourt, P., Dyer, S., Thiel, M., Hale, A., Chan, S.Y., 2014. Rapid up-regulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. J. Appl. Physiol. 116 (5), 522–531. Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., van Deursen, J.M., 2011. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236. Banzet, S., Chennaoui, M., Girard, O., Racinais, S., Drogou, C., Chalabi, H., Koulmann, N., 2013. Changes in circulating microRNAs levels with exercise modality. J. Appl. Q4 Physiol.. Bartel, D.P., 2009. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233. Beavers, K.M., Beavers, D.P., Houston, D.K., Harris, T.B., Hue, T.F., Koster, A., Newman, A.B., Simonsick, E.M., Studenski, S.A., Nicklas, B.J., Kritchevsky, S.B., 2013. Associations between body composition and gait-speed decline: results from the Health, Aging, and Body Composition study. Am. J. Clin. Nutr. 97, 552–560.


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Bhaumik, D., Scott, G.K., Schokrpur, S., Patil, C.K., Orjalo, A.V., Rodier, F., Lithgow, G.J., Campisi, J., 2009. MicroRNAs miR-146a/b negatively modulate the senescenceassociated inflammatory mediators IL-6 and IL-8. Aging (Albany, NY) 1, 402–411. Boutet, S.C., Cheung, T.H., Quach, N.L., Liu, L., Prescott, S.L., Edalati, A., Iori, K., Rando, T.A., 2012. Alternative polyadenylation mediates microRNA regulation of muscle stem cell function. Cell Stem Cell 10, 327–336. Bye, A., Røsjø, H., Aspenes, S.T., Condorelli, G., Omland, T., Wisløff, U., 2013. Circulating microRNAs and aerobic fitness – the HUNT-study. PLoS ONE 8, e57496. Chaillou, T., Lee, J.D., England, J.H., Esser, K.A., McCarthy, J.J., 2013. Time course of gene expression during mouse skeletal muscle hypertrophy. J. Appl. Physiol. 115 (7), 1065–1074. Chen, G.-Q., Lian, W.-J., Wang, G.-M., Wang, S., Yang, Y.-Q., Zhao, Z.-W., 2012. Altered microRNA expression in skeletal muscle results from high-fat diet-induced insulin resistance in mice. Mol. Med. Rep. 5, 1362–1368. Chen, J.-F., Mandel, E.M., Thomson, J.M., Wu, Q., Callis, T.E., Hammond, S.M., Conlon, F.L., Wang, D.-Z., 2006. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 38, 228–233. Chen, X., Gao, C., Li, H., Huang, L., Sun, Q., Dong, Y., Tian, C., Gao, S., Dong, H., Guan, D., Hu, X., Zhao, S., Li, L., Zhu, L., Yan, Q., Zhang, J., Zen, K., Zhang, C.-Y., 2010. Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. Cell Res. 20, 1128–1137. Chen, Y., Gelfond, J., McManus, L.M., Shireman, P.K., 2011. Temporal microRNA expression during in vitro myogenic progenitor cell proliferation and differentiation: regulation of proliferation by miR-682. Physiol. Genomics 43, 621–630. Cheung, T.H., Quach, N.L., Charville, G.W., Liu, L., Park, L., Edalati, A., Yoo, B., Hoang, P., Rando, T.A., 2012. Maintenance of muscle stem-cell quiescence by microRNA489. Nature 482, 524–528. Cruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., Boirie, Y., Cederholm, T., Landi, F., Martin, F.C., Michel, J.-P., Rolland, Y., Schneider, S.M., Topinková, E., Vandewoude, M., Zamboni, M., 2010. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39, 412–423. Davidsen, P.K., Gallagher, I.J., Hartman, J.W., Tarnopolsky, M.A., Dela, F., Helge, J.W., Timmons, J.A., Phillips, S.M., 2011. High responders to resistance exercise training demonstrate differential regulation of skeletal muscle microRNA expression. J. Appl. Physiol. 110, 309–317. De Lencastre, A., Pincus, Z., Zhou, K., Kato, M., Lee, S.S., Slack, F.J., 2010. MicroRNAs both promote and antagonize longevity in C. elegans. Curr. Biol. 20, 2159–2168. Delmonico, M.J., Harris, T.B., Visser, M., Park, S.W., Conroy, M.B., Velasquez-Mieyer, P., Boudreau, R., Manini, T.M., Nevitt, M., Newman, A.B., Goodpaster, B.H., 2009. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am. J. Clin. Nutr. 90, 1579–1585. Dey, B.K., Gagan, J., Yan, Z., Dutta, A., 2012. miR-26a is required for skeletal muscle differentiation and regeneration in mice. Genes Dev. 26, 2180–2191. Dimmeler, S., Nicotera, P., 2013. MicroRNAs in age-related diseases. EMBO Mol. Med. 5, 180–190. Djuranovic, S., Nahvi, A., Green, R., 2012. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science 336, 237–240. Do, G.-M., Jung, U.J., Park, H.-J., Kwon, E.-Y., Jeon, S.-M., McGregor, R.A., Choi, M.-S., 2012. Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP-activated protein kinase and its downstream targets in db/db mice. Mol. Nutr. Food Res. 56, 1282–1291. Donaldson, A., Natanek, S.A., Lewis, A., Man, W.D.-C., Hopkinson, N.S., Polkey, M.I., Kemp, P.R., 2013. Increased skeletal muscle-specific microRNA in the blood of patients with COPD. Thorax 68, 1140–1149. Drummond, M.J., Glynn, E.L., Fry, C.S., Dhanani, S., Volpi, E., Rasmussen, B.B., 2009. Essential amino acids increase microRNA-499, -208b, and -23a and downregulate myostatin and myocyte enhancer factor 2C mRNA expression in human skeletal muscle. J. Nutr. 139, 2279–2284. Drummond, M.J., McCarthy, J.J., Fry, C.S., Esser, K.A., Rasmussen, B.B., 2008. Aging differentially affects human skeletal muscle microRNA expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids. Am. J. Physiol. Endocrinol. Metab. 295, E1333–E1340. Drummond, M.J., McCarthy, J.J., Sinha, M., Spratt, H.M., Volpi, E., Esser, K.A., Rasmussen, B.B., 2011. Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol. Genomics 43, 595–603. Eisenberg, I., Eran, A., Nishino, I., Moggio, M., Lamperti, C., Amato, A.A., Lidov, H.G., Kang, P.B., North, K.N., Mitrani-Rosenbaum, S., Flanigan, K.M., Neely, L.A., Whitney, D., Beggs, A.H., Kohane, I.S., Kunkel, L.M., 2007. Distinctive patterns of microRNA expression in primary muscular disorders. Proc. Natl. Acad. Sci. U. S. A. 104, 17016–17021. Evans, W.J., 2010. Skeletal muscle loss: cachexia, sarcopenia, and inactivity. Am. J. Clin. Nutr. 91, 1123S–1127S. Evans, W.J., Lexell, J., 1995. Human aging, muscle mass, and fiber type composition. J. Gerontol. A Biol. Sci. Med. Sci. 50A, 11–16. Forterre, A., Jalabert, A., Chikh, K., Pesenti, S., Euthine, V., Granjon, A., Errazuriz, E., Lefai, E., Vidal, H., Rome, S., 2014. Myotube-derived exosomal miRNAs downregulate Sirtuin1 in myoblasts during muscle cell differentiation. Cell Cycle 13, 78–89. Fredriksson, K., Tjäder, I., Keller, P., Petrovic, N., Ahlman, B., Schéele, C., Wernerman, J., Timmons, J.A., Rooyackers, O., 2008. Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure. PLoS ONE 3, e3686.

Friedman, R.C., Farh, K.K.-H., Burge, C.B., Bartel, D.P., 2009. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105. Gallagher, I.J., Scheele, C., Keller, P., Nielsen, A.R., Remenyi, J., Fischer, C.P., Roder, K., Babraj, J., Wahlestedt, C., Hutvagner, G., Pedersen, B.K., Timmons, J.A., 2010. Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes. Genome Med. 2, 9. Gan, Z., Rumsey, J., Hazen, B.C., Lai, L., Leone, T.C., Vega, R.B., Xie, H., Conley, K.E., Auwerx, J., Smith, S.R., Olson, E.N., Kralli, A., Kelly, D.P., 2013. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. J. Clin. Invest. 123 (6), 2564–2575. Goljanek-Whysall, K., Pais, H., Rathjen, T., Sweetman, D., Dalmay, T., Münsterberg, A., 2012. Regulation of multiple target genes by miR-1 and miR-206 is pivotal for C2C12 myoblast differentiation. J. Cell. Sci. 125, 3590–3600. Goodpaster, B.H., Park, S.W., Harris, T.B., Kritchevsky, S.B., Nevitt, M., Schwartz, A.V., Simonsick, E.M., Tylavsky, F.A., Visser, M., Newman, A.B., 2006. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J. Gerontol. A Biol. Sci. Med. Sci. 61, 1059–1064. Grillari, J., Grillari-Voglauer, R., 2010. Novel modulators of senescence, aging, and longevity: small non-coding RNAs enter the stage. Exp. Gerontol. 45, 302–311. Güller, I., Russell, A.P., 2010. MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J. Physiol. (Lond.) 588, 4075–4087. Hackl, M., Brunner, S., Fortschegger, K., Schreiner, C., Micutkova, L., Mück, C., Laschober, G.T., Lepperdinger, G., Sampson, N., Berger, P., Herndler-Brandstetter, D., Wieser, M., Kühnel, H., Strasser, A., Rinnerthaler, M., Breitenbach, M., Mildner, M., Eckhart, L., Tschachler, E., Trost, A., Bauer, J.W., Papak, C., Trajanoski, Z., Scheideler, M., Grillari-Voglauer, R., Grubeck-Loebenstein, B., Jansen-Dürr, P., Grillari, J., 2010. miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell 9, 291–296. Hamrick, M.W., Herberg, S., Arounleut, P., He, H.-Z., Shiver, A., Qi, R.-Q., Zhou, L., Isales, C.M., Mi, Q.-S., 2010. The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice. Biochem. Biophys. Res. Commun. 400, 379–383. Hata, T., Murakami, K., Nakatani, H., Yamamoto, Y., Matsuda, T., Aoki, N., 2010. Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem. Biophys. Res. Commun. 396, 528–533. Hawke, T.J., Garry, D.J., 2001. Myogenic satellite cells: physiology to molecular biology. J. Appl. Physiol. 91, 534–551. Hazarika, S., Farber, C.R., Dokun, A.O., Pitsillides, A.N., Wang, T., Lye, R.J., Annex, B.H., 2013. MicroRNA-93 controls perfusion recovery after hindlimb ischemia by modulating expression of multiple genes in the cell cycle pathway. Circulation 127, 1818–1828. Izumi, H., Kosaka, N., Shimizu, T., Sekine, K., Ochiya, T., Takase, M., 2013. Purification of RNA from milk whey. Methods Mol. Biol. 1024, 191–201. Jiang, L.Q., Franck, N., Egan, B., Sjögren, R.J.O., Katayama, M., Duque-Guimaraes, D., Arner, P., Zierath, J.R., Krook, A., 2013. Autocrine role of interleukin-13 on skeletal muscle glucose metabolism in type 2 diabetic patients involves microRNA let-7. Am. J. Physiol. Endocrinol. Metab. 305, E1359–E1366. Kaminski, J., Lançon, A., Aires, V., Limagne, E., Tili, E., Michaille, J.-J., Latruffe, N., 2012. Resveratrol initiates differentiation of mouse skeletal muscle-derived C2C12 myoblasts. Biochem. Pharmacol. 84, 1251–1259. Kato, M., Slack, F.J., 2013. Ageing and the small, non-coding RNA world. Ageing Res. Rev. 12, 429–435. Kim, V.N., Han, J., Siomi, M.C., 2009. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126–139. Koning, M., Werker, P.M.N., van Luyn, M.J.A., Krenning, G., Harmsen, M.C., 2012. A global downregulation of microRNAs occurs in human quiescent satellite cells during myogenesis. Differentiation 84, 314–321. Kozomara, A., Griffiths-Jones, S., 2011. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157. Kukreti, H., Amuthavalli, K., Harikumar, A., Sathiyamoorthy, S., Feng, P.Z., Anantharaj, R., Tan, S.L.K., Lokireddy, S., Bonala, S., Sriram, S., McFarlane, C., Kambadur, R., Sharma, M., 2013. Muscle-specific microRNA1 (miR1) targets heat shock protein 70 (HSP70) during dexamethasone-mediated atrophy. J. Biol. Chem. 288, 6663–6678. Lagos-Quintana, M., Rauhut, R., Lendeckel, W., Tuschl, T., 2001. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858. Lançon, A., Kaminski, J., Tili, E., Michaille, J.-J., Latruffe, N., 2012. Control of MicroRNA expression as a new way for resveratrol to deliver its beneficial effects. J. Agric. Food Chem. 60, 8783–8789. Lecker, S.H., Jagoe, R.T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S.R., Mitch, W.E., Goldberg, A.L., 2004. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Rådmark, O., Kim, S., Kim, V.N., 2003. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419. Lewis, A., Riddoch-Contreras, J., Natanek, S.A., Donaldson, A., Man, W.D.-C., Moxham, J., Hopkinson, N.S., Polkey, M.I., Kemp, P.R., 2012. Downregulation of the serum response factor/miR-1 axis in the quadriceps of patients with COPD. Thorax 67, 26–34. Li, H., Zhang, Z., Zhou, X., Wang, Z., Wang, G., Han, Z., 2011a. Effects of microRNA-143 in the differentiation and proliferation of bovine intramuscular preadipocytes. Mol. Biol. Rep. 38, 4273–4280. Li, N., Bates, D.J., An, J., Terry, D.A., Wang, E., 2011b. Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol. Aging 32, 944–955.


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Lim, L.P., Lau, N.C., Garrett-Engele, P., Grimson, A., Schelter, J.M., Castle, J., Bartel, D.P., Linsley, P.S., Johnson, J.M., 2005. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773. Liu, N., Williams, A.H., Kim, Y., McAnally, J., Bezprozvannaya, S., Sutherland, L.B., Richardson, J.A., Bassel-Duby, R., Olson, E.N., 2007. An intragenic MEF2dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proc. Natl. Acad. Sci. U. S. A. 104, 20844–20849. Liu, N., Williams, A.H., Maxeiner, J.M., Bezprozvannaya, S., Shelton, J.M., Richardson, J.A., Bassel-Duby, R., Olson, E.N., 2012. microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. J. Clin. Invest. 122, 2054–2065. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153, 1194–1217. Lund, E., Güttinger, S., Calado, A., Dahlberg, J.E., Kutay, U., 2004. Nuclear export of microRNA precursors. Science 303, 95–98. Martinez, I., Cazalla, D., Almstead, L.L., Steitz, J.A., DiMaio, D., 2011. miR-29 and miR30 regulate B-Myb expression during cellular senescence. Proc. Natl. Acad. Sci. U. S. A. 108, 522–527. McCarthy, J.J., Esser, K.A., Andrade, F.H., 2007. MicroRNA-206 is overexpressed in the diaphragm but not the hindlimb muscle of mdx mouse. Am. J. Physiol. Cell Physiol. 293, C451–C457. McCarthy, J.J., Esser, K.A., Peterson, C.A., Dupont-Versteegden, E.E., 2009. Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy. Physiol. Genomics 39, 219–226. McGregor, R.A., Choi, M.S., 2011. microRNAs in the regulation of adipogenesis and obesity. Curr. Mol. Med. 11, 304–316. McGregor, R.A., Poppitt, S.D., 2013. Milk protein for improved metabolic health: a review of the evidence. Nutr. Metab. 10, 46. Mercken, E.M., Majounie, E., Ding, J., Guo, R., Kim, J., Bernier, M., Mattison, J., Cookson, M.R., Gorospe, M., de Cabo, R., Abdelmohsen, K., 2013. Age-associated miRNA Alterations in Skeletal Muscle from Rhesus Monkeys reversed by caloric restriction. Aging (Albany, NY) 5 (9), 692–703. Milenkovic, D., Jude, B., Morand, C., 2013. miRNA as molecular target of polyphenols underlying their biological effects. Free Radic. Biol. Med. 64, 40–51. Mooren, F.C., Viereck, J., Krüger, K., Thum, T., 2014. Circulating micrornas as potential biomarkers of aerobic exercise capacity. Am. J. Physiol. Heart Circ. Physiol. 306, H557–H563. Motohashi, N., Alexander, M.S., Shimizu-Motohashi, Y., Myers, J.A., Kawahara, G., Kunkel, L.M., 2013. Regulation of IRS1/Akt insulin signaling by microRNA-128a during myogenesis. J. Cell. Sci. 126, 2678–2691. Mueller, M., Breil, F.A., Lurman, G., Klossner, S., Flück, M., Billeter, R., Däpp, C., Hoppeler, H., 2011. Different molecular and structural adaptations with eccentric and conventional strength training in elderly men and women. Gerontology 57, 528–538. Nakasa, T., Ishikawa, M., Shi, M., Shibuya, H., Adachi, N., Ochi, M., 2010. Acceleration of muscle regeneration by local injection of muscle-specific microRNAs in rat skeletal muscle injury model. J. Cell. Mol. Med. 14, 2495–2505. Nielsen, S., Scheele, C., Yfanti, C., Akerström, T., Nielsen, A.R., Pedersen, B.K., Laye, M.J., Laye, M., 2010. Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. J. Physiol. (Lond.) 588, 4029–4037. Oishi, T., Uezumi, A., Kanaji, A., Yamamoto, N., Yamaguchi, A., Yamada, H., Tsuchida, K., 2013. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS ONE 8, e56641. Olivieri, F., Spazzafumo, L., Santini, G., Lazzarini, R., Albertini, M.C., Rippo, M.R., Galeazzi, R., Abbatecola, A.M., Marcheselli, F., Monti, D., Ostan, R., Cevenini, E., Antonicelli, R., Franceschi, C., Procopio, A.D., 2012. Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. Mech. Ageing Dev. 133, 675–685. Paddon-Jones, D., Short, K.R., Campbell, W.W., Volpi, E., Wolfe, R.R., 2008. Role of dietary protein in the sarcopenia of aging. Am. J. Clin. Nutr. 87, 1562S–1566S. Prats-Puig, A., Ortega, F.J., Mercader, J.M., Moreno-Navarrete, J.M., Moreno, M., Bonet, N., Ricart, W., López-Bermejo, A., Fernández-Real, J.M., 2013. Changes in circulating microRNAs are associated with childhood obesity. J. Clin. Endocrinol. Metab. 98, E1655–E1660. Pritchard, C.C., Kroh, E., Wood, B., Arroyo, J.D., Dougherty, K.J., Miyaji, M.M., Tait, J.F., Tewari, M., 2012. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev. Res. (Phila.) 5, 492–497. Ringholm, S., Biensø, R.S., Kiilerich, K., Guadalupe-Grau, A., Aachmann-Andersen, N.J., Saltin, B., Plomgaard, P., Lundby, C., Wojtaszewski, J.F.P., Calbet, J.A., Pilegaard, H., 2011. Bed rest reduces metabolic protein content and abolishes exercise-induced mRNA responses in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 301, E649–E658.

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Roberts, T.C., Blomberg, K.E.M., McClorey, G., El Andaloussi, S., Godfrey, C., Betts, C., Coursindel, T., Gait, M.J., Smith, C.I.E., Wood, M.J.A., 2012. Expression analysis in multiple muscle groups and serum reveals complexity in the microRNA transcriptome of the mdx mouse with implications for therapy. Mol. Ther. Nucleic Acids 1, e39. ˜ D.P., Raza, S.R., FreRodier, F., Coppé, J.-P., Patil, C.K., Hoeijmakers, W.A.M., Munoz, und, A., Campeau, E., Davalos, A.R., Campisi, J., 2009. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979. Rottiers, V., Näär, A.M., 2012. MicroRNAs in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 13, 239–250. Safdar, A., Abadi, A., Akhtar, M., Hettinga, B.P., Tarnopolsky, M.A., 2009. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PLoS ONE 4, e5610. Selbach, M., Schwanhäusser, B., Thierfelder, N., Fang, Z., Khanin, R., Rajewsky, N., 2008. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63. Shefer, G., Van de Mark, D.P., Richardson, J.B., Yablonka-Reuveni, Z., 2006. Satellitecell pool size does matter: defining the myogenic potency of aging skeletal muscle. Dev. Biol. 294, 50–66. Smith-Vikos, T., Slack, F.J., 2012. MicroRNAs and their roles in aging. J. Cell Sci. 125, 7–17. Sood, P., Krek, A., Zavolan, M., Macino, G., Rajewsky, N., 2006. Cell-type-specific signatures of microRNAs on target mRNA expression. Proc. Natl. Acad. Sci. U. S. A. 103, 2746–2751. Suetta, C., Frandsen, U., Mackey, A.L., Jensen, L., Hvid, L.G., Beyer, M.L., Petersson, S.J., Schrøder, H.D., Andersen, J.L., Aagaard, P., Schjerling, P., Kjaer, M., 2013. Aging is associated with diminished muscle re-growth and myogenic precursor cell expansion in the early recovery phase after immobility-induced atrophy in human skeletal muscle. J. Physiol. (Lond.) 591, 3789–3804. Sun, Q., Chen, X., Yu, J., Zen, K., Zhang, C.-Y., Li, L., 2013. Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum. Protein Cell 4, 197–210. Trajkovski, M., Hausser, J., Soutschek, J., Bhat, B., Akin, A., Zavolan, M., Heim, M.H., Stoffel, M., 2011. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653. Uhlemann, M., Möbius-Winkler, S., Fikenzer, S., Adam, J., Redlich, M., Möhlenkamp, S., Hilberg, T., Schuler, G.C., Adams, V., 2014. Circulating microRNA-126 increases after different forms of endurance exercise in healthy adults. Eur. J. Prev. Cardiol. 21, 484–491. Verdijk, L.B., Koopman, R., Schaart, G., Meijer, K., Savelberg, H.H.C.M., Loon, L.J.C. van, 2007. Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. Am. J. Physiol. Endocrinol. Metab. 292, E151–E157. Vettor, R., Milan, G., Franzin, C., Sanna, M., De Coppi, P., Rizzuto, R., Federspil, G., 2009. The origin of intermuscular adipose tissue and its pathophysiological implications. Am. J. Physiol. Endocrinol. Metab. 297, E987–E998. Wada, S., Kato, Y., Okutsu, M., Miyaki, S., Suzuki, K., Yan, Z., Schiaffino, S., Asahara, H., Ushida, T., Akimoto, T., 2011. Translational suppression of atrophic regulators by microRNA-23a integrates resistance to skeletal muscle atrophy. J. Biol. Chem. 286, 38456–38465. Wang, K., Li, H., Yuan, Y., Etheridge, A., Zhou, Y., Huang, D., Wilmes, P., Galas, D., 2012. The complex exogenous RNA spectra in human plasma: an interface with human gut biota? PLoS ONE 7, e51009. Wang, X.H., 2013. MicroRNA in myogenesis and muscle atrophy. Curr. Opin. Clin. Nutr. Metab. Care 16, 258–266. Witwer, K.W., 2012. XenomiRs and miRNA homeostasis in health and disease: evidence that diet and dietary miRNAs directly and indirectly influence circulating miRNA profiles. RNA Biol. 9, 1147–1154. Xu, L., Yang, B.-F., Ai, J., 2013. MicroRNA transport: a new way in cell communication. J. Cell. Physiol. 228, 1713–1719. Yuasa, K., Hagiwara, Y., Ando, M., Nakamura, A., Takeda, S., Hijikata, T., 2008. MicroRNA-206 is highly expressed in newly formed muscle fibers: implications regarding potential for muscle regeneration and maturation in muscular dystrophy. Cell Struct. Funct. 33, 163–169. Zhou, Q., Li, M., Wang, X., Li, Q., Wang, T., Zhu, Q., Zhou, X., Wang, X., Gao, X., Li, X., 2012. Immune-related microRNAs are abundant in breast milk exosomes. Int. J. Biol. Sci. 8, 118–123. Zhu, H., Shyh-Chang, N., Segrè, A.V., Shinoda, G., Shah, S.P., Einhorn, W.S., Takeuchi, A., Engreitz, J.M., Hagan, J.P., Kharas, M.G., Urbach, A., Thornton, J.E., Triboulet, R., Gregory, R.I., Consortium, D.I.A.G.R.A.M, Investigators, M.A.G.I.C., Altshuler, D., Daley, G.Q., 2011. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94.


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Exercise Promotes Healthy Aging of Skeletal Muscle.

Role of microRNAs in skeletal muscle hypertrophy.

The role of microRNAs in skeletal muscle health and disease.

Editorial: Redox Regulation in Skeletal Muscle Aging and Exercise.

Role of microRNAs in skeletal muscle development and rhabdomyosarcoma (review).

MicroRNAs, heart failure, and aging: potential interactions with skeletal muscle.

Early skeletal muscle adaptations to short-term high-fat diet in humans before changes in insulin sensitivity.

Statin-induced Myopathy in Skeletal Muscle: the Role of Exercise.

Aging and the Skeletal Muscle Angiogenic Response to Exercise in Women.

Skeletal muscle aging: influence of oxidative stress and physical exercise.

nutrient-sensing pathways during metabolic adaptation to fasting in healthy humans.

Does skeletal muscle have an 'epi'-memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise.

Role of α-adrenergic vasoconstriction in regulating skeletal muscle blood flow and vascular conductance during forearm exercise in ageing humans.

Skeletal muscle myofilament adaptations to aging, disease, and disuse and their effects on whole muscle performance in older adult humans.

MicroRNAs in skeletal muscle and their regulation with exercise, ageing, and disease.

Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials.

Amino acid changes during transition to a vegan diet supplemented with fish in healthy humans.

Lactate kinetics and mitochondrial respiration in skeletal muscle of healthy humans under influence of adrenaline.

The pleiotropic effect of physical exercise on mitochondrial dynamics in aging skeletal muscle.

Muscle chemoreflexes and exercise in humans.

Effect of endurance exercise on microRNAs in myositis skeletal muscle-A randomized controlled study.

Changes in the electrocardiographic response to exercise in healthy women.

Effects of aging, exercise, and disease on force transfer in skeletal muscle.

Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle.