REVIEW URRENT C OPINION
Myopathic characteristics in septic mechanically ventilated patients Claire E. Baldwin a,b and Andrew D. Bersten c,d
Purpose of review Survivors of a critical illness may experience poor physical function and quality of life as a result of reduced skeletal muscle mass and strength during their acute illness. Patients diagnosed with sepsis are particularly at risk, and mechanical ventilation may result in diaphragm dysfunction. Interest in the interaction of these conditions is both growing and important to understand for individualized patient care. Recent findings This review describes developments in the presentation of both diaphragm and limb myopathy in critical illness, as measured from muscle biopsy and at the bedside with various imaging and strength-testing modalities. The influence of unloading of the diaphragm with mechanical ventilation and peripheral muscles with immobilization in septic patients has been recently questioned. Systemic inflammation appears to primarily accelerate and accentuate dysfunction, which may be remedied by early mobilization and augmented with developing muscle and/or nerve stimulation techniques. Summary Many acute muscle changes in septic patients are likely to stem from pre-existing impairments, which should provide context for clinical evaluations of strength. During illness, sarcolemmal injury promotes a cascade of intra-cellular abnormalities. As unique characteristics of ICU-acquired weakness and differential effects on muscle groups are understood, early diagnosis and management should be facilitated. Keywords diaphragm dysfunction, ICU-acquired weakness, muscle atrophy, quadriceps, sepsis
INTRODUCTION Sepsis and mechanical ventilation can cause skeletal muscle wasting and weakness in the critically ill, for which effects on the diaphragm are the most interesting but the least well understood. Although these conditions share pathophysiologic commonalities like oxidative stress and contractile dysfunction, they also differ in some aspects; controlled mechanical ventilation reduces mitochondrial biogenesis following metabolic oversupply [1], but during sepsis, this occurs due to metabolite depletion [2]. Recently, the interaction between sepsis and mechanical ventilation has been described as additive to create the ‘perfect storm’, but with limited data, this cannot be assumed [3]. Effects may also differ according to the dominant stimulus (inflammation versus inactivity), muscle properties, the time course of illness and commencement of interventions amidst developing or pre-existing injury. A review of developments in muscle pathophysiology is followed by a discussion of the inactivity hypothesis, differential effects on respiratory and peripheral www.co-clinicalnutrition.com
muscles, and an overview of clinical measurements and interventional studies.
PATHOPHYSIOLOGY: PROTEIN BALANCE, GLUCOSE METABOLISM, EXCITATION– CONTRACTION COUPLING Understanding the most proximal events in skeletal muscle inflammatory and inactivity cascades has been a focus of recent literature for ICU patients a
International Centre for Allied Health Evidence and School of Health Sciences, University of South Australia, Adelaide, bPhysiotherapy Department, Flinders Medical Centre, Bedford Park, cDepartment of Critical Care Medicine, School of Medicine, Faculty of Health Sciences, Flinders University, Bedford Park and dIntensive and Critical Care Unit, Flinders Medical Centre, Bedford Park, South Australia, Australia Correspondence to Professor Andrew D. Bersten, Intensive and Critical Care Unit, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. Tel: +61 8 8204 5511; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2015, 18:240–247 DOI:10.1097/MCO.0000000000000165 Volume 18 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Myopathy with sepsis and mechanical ventilation Baldwin and Bersten
KEY POINTS Systemic inflammation is a stronger influence than immobility on muscle weakness and wasting in septic ICU patients. Although alterations in diaphragm muscle properties with mechanical ventilation and sepsis are conflicting, there appears to be targeting of the quadriceps. The validation of nonvolitional measurements of respiratory and peripheral muscle function should facilitate their adoption to clinical practice, to improve the recognition of phenotypes of weakness and functional limitations.
with descriptions of suppressed, normal and increased protein synthesis, combined with increased protein degradation (especially of myosin in type II fibres), resulting in catabolism [4,5] (Fig. 1). A series of studies of mechanically ventilated patients at risk of critical illness myopathy (CIM) has significantly progressed understanding [6 ,7,8]. In particular, vastus lateralis biopsies at day 5 have confirmed increased activity of the major systems for protein degradation [8] (Fig. 1). Moreover, the role of nuclear factor (NF)-kB signalling has been studied in septic transgenic mice that over-express the muscle-specific I kappa B alpha super repressor [9,10]. It appears that NF-kB inhibition can attenuate sepsis-induced diaphragm force loss, possibly through reducing muscle ring finger-1 (MuRF-1), atrogin-1 [9] and/or light chain 3 phosphatidylethanolamine conjugate levels that suggest less autophagosome formation [10]. This adds to the understanding of NF-kB signalling in other conditions associated with atrophy, including unloading of the limbs through immobilization [11] and the diaphragm with controlled mechanical ventilation [12]. Moreover, autophagy has been described as a beneficial adaptive mechanism in ventilator-induced diaphragm dysfunction [13]. Similarly, higher autophagy in patients tolerating macronutrient deficit without parenteral nutrition for the first week of ICU admission may actually reflect better ‘housekeeping’ of degraded proteins and be associated with less weakness [14 ]. A complex interplay between autophagy and necrosis may partially explain conflicting findings as to the presence [15] or absence [8] of necrosis on vastus lateralis biopsy from ICU patients. Although iatrogenic necrosis cannot be excluded [16], necrosis was associated with macrophage infiltration [15]. While inflammation has been previously described with necrosis [4] and macrophage infiltration to occur in approximately 40% of biopsies as either isolated cells or small clustered &&
&
infiltrates [17], the relevance of M1 or M2 macrophage phenotypes is yet to be determined. On the other side of muscular protein balance, one study has reported unchanged synthesis in the first few days of illness, but a slight increase by 1 week [15]. Yet, more interesting than small alterations in the fractional synthesis rate of mixed muscle protein [15] are findings that contractile myosin heavy chain synthesis is specifically impaired [8,14 ] (Fig. 1). This is consistent with previous research [4,5], appears to be unaffected by nutritional regimen [14 ] and may be most marked in fast-twitch muscles [18]. With respect to glucose metabolism, hyperglycaemia can reduce diaphragm-specific force as demonstrated in an insulin-dependent model of diabetes [19]. Commentary on this result has drawn a parallel between hyperglycaemia and sepsisinduced diaphragm dysfunction, suggesting that chronic illnesses may enhance responses to critical illness [20]. However, blood glucose was not related to trans-diaphragmatic twitch pressures in 57 mechanically ventilated patients [21 ], consistent with a study in which abnormalities in glucose transporter type 4 (GLUT4) transport were described as more relevant than circulating glucose and intact upstream insulin signalling to Akt phosphorylation [6 ] (Fig. 1). GLUT4 translocation to the sarcolemma is a critical step in glucose uptake by skeletal muscle, and the localization of GLUT4 to perinuclear spaces was an exclusive differentiating feature between CIM and non-CIM diagnosed patients. Glucose responses, as determined by anaerobic metabolites, may also differ between endotoxic and haemorrhagic shock [22], suggesting that caution should be exerted when extrapolating findings between shock models. Another unique finding in CIM versus non-CIM patients is elevation in leg muscle serum amyloid A (SAA) proteins at day 5 [7]. SAA is an acute-phase response protein and marker for insulin resistance that appears to be produced locally by muscle in critical illness. Still, patients without CIM may have elevated SAA after more prolonged illness, suggesting accelerated changes in CIM that would still be observed in a presentation consistent with immobility. Issues with glucose signalling at the sarcolemma point to other impediments at both the myocyte membrane and with excitation contraction coupling. Starting with the motor end-plate, a rat model of acute and chronic sepsis has reported changes in nicotinic acetylcholine receptor (AChR) expression to a greater density of immature isoforms (g and a7) (Fig. 2a), similar to that observed with reduced neural input [23]. This is consistent with increased g-AChR mRNA in the vastus lateralis, but &
&
&&
&&
1363-1950 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-clinicalnutrition.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
241
Translational research in wasting diseases
degradation /~/synthesis
CATABOLISM extracellular
cytoplasm
Ca2+
IGF-1 receptor
Caplins
contraction
glucose sarcolemma
sarcomere E1 Ub Z
Z
cytoplasm
PI3K ATP
E2 Ub
E2
E3’s -MuRF-1 Ub
Akt
NF-kB
-atrogin-1 AMP
actin/myosin Ub
peptides +
ATP AMPK
26 S
Ub lysosome
Downstream LC3
pathways of
GLUT4 vesicle
protein synthesis
autophagolysosome
autophagosome
phagophore
MyHC synthesis
nucleus
FIGURE 1. Simplified schematic of the major systems for protein degradation and pathways related to both protein synthesis and glucose transport in the skeletal muscle of critically ill patients. Calpains can cleave sarcomere proteins including actin, myosin (MyHC), titin and nebulin for degradation by the ubiquitin proteasome pathway (UPP). Ubiquitin (Ub) is activated and transferred to a conjugating enzyme before muscle specific E3 ligases muscle ring finger-1 (MuRF-1) and atrogin-1 mark proteins for degradation. Poly-ubiquitin-tagged proteins are recognized by the 26S proteasome where they are unfolded and de-ubiquitinated for a net gain of adenosine triphosphate (ATP). Lysosomes are linked to the autophagy-lysosome pathway (ALP) as double membrane vesicles (autophagosomes) form around cellular constituents such as mitochondria before fusion with lysosomes where their contents are degraded. Basal autophagy is important for cell survival and recycling old or damaged organelles. Excessive autophagy induces pathological changes such as apoptosis. Nuclear factor kB (NF-kB) transcription factors mediate immunity and inflammation, and downstream signalling can promote protein degradation by the ALP and UPP. The balance between protein synthesis and degradation is regulated in part by Akt (protein kinase B). The induction of phosphoinositide 3-kinase (PI3K) and Akt phosphorylation follows upstream signalling such as through the insulingrowth factor-1 (IGF-1) receptor. Both insulin-dependent and insulin-independent [5’-adenosine monophosphate-activated protein kinase (AMPK)] pathways can influence intracellular GLUT4 transport. Adapted, in part, with permission from [4,15].
not rectus abdominus of ICU patients with abnormal spontaneous electrical activity, indicating CIM [4]. Longer channel-opening times of immature AChRs may affect membrane depolarization and other aspects of calcium signalling. For example, the sarcolemmal dihydropyridine receptor skeletal muscle isoform (DHPRa1s) receptor (skeletal muscle 242
www.co-clinicalnutrition.com
sub-type) of the transverse tubule (T-tubule) is mechanically coupled to the RyR1 Ca2þ channel on the sarcoplasmic reticulum of the skeletal muscle (Fig. 2b). The expression of both DHPRa1s and RyR1 has been reported to be reduced in the diaphragm of rats 24 h after induction of intra-peritoneal sepsis [24]. Furthermore, intra-cellular interleukin (IL)-1a Volume 18 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Myopathy with sepsis and mechanical ventilation Baldwin and Bersten
Motor neuron - trophic influences - axoplasmic transport
(a)
(b) sarcolemma γ
α7
ε
ε
ε
Ca2+
ACh receptors
DHPR α1s
(c)
RyR1 receptor Mitochondria SR ATP ROS
Ca2+
Force
T-tubule mPTP ROS + RCS carbonylated proteins degradation
FIGURE 2. Simplified schematic of pathological changes in skeletal muscle with critical illness at (a) the motor end plate by expression of immature acetylcholine receptor isoforms, (b) calcium leak from the sarcoplasmic reticulum and (c) formation of nonspecific permeability transition pores on mitochondria that open pathologically in response to conditions that include elevated calcium. Mitochondria are a significant source of reactive oxygen species that contribute to oxidative stress in critical illness and subsequent protein degradation. ACh, acetylcholine; ATP, adenosine triphosphate; DHPRa1s, dihydropyridine receptor skeletal muscle isoform; mPTP, mitochondrial permeability transition pore; RCS, reactive carbonyl species; ROS, reactive oxygen species; RyR1, ryanodine receptor skeletal muscle isoform; SR, sarcoplasmic reticulum; T-tubule, transverse tubule; g, fetal ACh receptor; a7, neuronal ACh receptor; e, adult ACh receptor.
may directly block RyR1 by stabilizing its normal Mg2þ inhibition, thereby suggesting how inflammation might unexpectedly reduce sarcoplasmic reticulum Ca2þ leak [25]. Excitation–contraction coupling has not been a focus of mechanical ventilation research, meaning that findings from diaphragm biopsy of 10 patients (mechanically ventilated 28–603 h for laparotomy/ thoracotomy) are novel [26 ]. Apart from force loss in type II fibres, they may require more calcium to generate force and Ca2þ sensitivity could be improved by a fast skeletal troponin activator. Similarly, a series of human and animal experiments suggest that abnormal resting sarcoplasmic reticulum Ca2þ leak and mechanical ventilation contractile dysfunction could be improved with a RyR1 stabilizer [27]. The intra-cellular effects of abnormal Ca2þ regulation include mitochondrial-free radical &
generation and activation of calpains; pathological opening of permeability transition pores of the inner mitochondrial membrane (Fig. 2c) has been observed in diaphragm and leg muscle of septic mice [10], and calpain-1 is elevated in leg muscle of patients by 2 weeks of ICU admission [8]. Calpain-1 can then cleave cytoskeletal proteins (Fig. 1) and particularly titin, which has recently been observed to be reduced after 2 days of mechanical ventilation in organ donors [28].
THE ROLES OF INFLAMMATION AND INACTIVITY Recently the role of inactivity as a dominant stimulus for diaphragm and limb dysfunction in the critically ill has been questioned [29–31]. While it is acknowledged that profound diaphragm
1363-1950 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-clinicalnutrition.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
243
Translational research in wasting diseases
wasting and weakness can occur with controlled mechanical ventilation in organ donors [28,32], these changes occur more rapidly than with unloading of limb muscles. Sieck and Mantilla [30] contend that inactivity per se does not result in diaphragm atrophy, and the removal of external loading without understanding the impact of motor neural activation (Fig. 2a) may affect interpretation of results. For peripheral muscle, wasting has been studied over the first week of ICU admission with ultrasound in a sample in which 49% had an admission diagnosis of sepsis [15]. Reductions in rectus femoris cross-sectional area (CSA) were greatest in patients with multiple as compared to single organ failure, which downgrades the proposed influence of inactivity as patients were effectively confined to bed. For the diaphragm, significant weakness has been demonstrated by reduced twitch pressures (
Myopathic characteristics in septic mechanically ventilated patients Claire E. Baldwin a,b and Andrew D. Bersten c,d
Purpose of review Survivors of a critical illness may experience poor physical function and quality of life as a result of reduced skeletal muscle mass and strength during their acute illness. Patients diagnosed with sepsis are particularly at risk, and mechanical ventilation may result in diaphragm dysfunction. Interest in the interaction of these conditions is both growing and important to understand for individualized patient care. Recent findings This review describes developments in the presentation of both diaphragm and limb myopathy in critical illness, as measured from muscle biopsy and at the bedside with various imaging and strength-testing modalities. The influence of unloading of the diaphragm with mechanical ventilation and peripheral muscles with immobilization in septic patients has been recently questioned. Systemic inflammation appears to primarily accelerate and accentuate dysfunction, which may be remedied by early mobilization and augmented with developing muscle and/or nerve stimulation techniques. Summary Many acute muscle changes in septic patients are likely to stem from pre-existing impairments, which should provide context for clinical evaluations of strength. During illness, sarcolemmal injury promotes a cascade of intra-cellular abnormalities. As unique characteristics of ICU-acquired weakness and differential effects on muscle groups are understood, early diagnosis and management should be facilitated. Keywords diaphragm dysfunction, ICU-acquired weakness, muscle atrophy, quadriceps, sepsis
INTRODUCTION Sepsis and mechanical ventilation can cause skeletal muscle wasting and weakness in the critically ill, for which effects on the diaphragm are the most interesting but the least well understood. Although these conditions share pathophysiologic commonalities like oxidative stress and contractile dysfunction, they also differ in some aspects; controlled mechanical ventilation reduces mitochondrial biogenesis following metabolic oversupply [1], but during sepsis, this occurs due to metabolite depletion [2]. Recently, the interaction between sepsis and mechanical ventilation has been described as additive to create the ‘perfect storm’, but with limited data, this cannot be assumed [3]. Effects may also differ according to the dominant stimulus (inflammation versus inactivity), muscle properties, the time course of illness and commencement of interventions amidst developing or pre-existing injury. A review of developments in muscle pathophysiology is followed by a discussion of the inactivity hypothesis, differential effects on respiratory and peripheral www.co-clinicalnutrition.com
muscles, and an overview of clinical measurements and interventional studies.
PATHOPHYSIOLOGY: PROTEIN BALANCE, GLUCOSE METABOLISM, EXCITATION– CONTRACTION COUPLING Understanding the most proximal events in skeletal muscle inflammatory and inactivity cascades has been a focus of recent literature for ICU patients a
International Centre for Allied Health Evidence and School of Health Sciences, University of South Australia, Adelaide, bPhysiotherapy Department, Flinders Medical Centre, Bedford Park, cDepartment of Critical Care Medicine, School of Medicine, Faculty of Health Sciences, Flinders University, Bedford Park and dIntensive and Critical Care Unit, Flinders Medical Centre, Bedford Park, South Australia, Australia Correspondence to Professor Andrew D. Bersten, Intensive and Critical Care Unit, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia. Tel: +61 8 8204 5511; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2015, 18:240–247 DOI:10.1097/MCO.0000000000000165 Volume 18 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Myopathy with sepsis and mechanical ventilation Baldwin and Bersten
KEY POINTS Systemic inflammation is a stronger influence than immobility on muscle weakness and wasting in septic ICU patients. Although alterations in diaphragm muscle properties with mechanical ventilation and sepsis are conflicting, there appears to be targeting of the quadriceps. The validation of nonvolitional measurements of respiratory and peripheral muscle function should facilitate their adoption to clinical practice, to improve the recognition of phenotypes of weakness and functional limitations.
with descriptions of suppressed, normal and increased protein synthesis, combined with increased protein degradation (especially of myosin in type II fibres), resulting in catabolism [4,5] (Fig. 1). A series of studies of mechanically ventilated patients at risk of critical illness myopathy (CIM) has significantly progressed understanding [6 ,7,8]. In particular, vastus lateralis biopsies at day 5 have confirmed increased activity of the major systems for protein degradation [8] (Fig. 1). Moreover, the role of nuclear factor (NF)-kB signalling has been studied in septic transgenic mice that over-express the muscle-specific I kappa B alpha super repressor [9,10]. It appears that NF-kB inhibition can attenuate sepsis-induced diaphragm force loss, possibly through reducing muscle ring finger-1 (MuRF-1), atrogin-1 [9] and/or light chain 3 phosphatidylethanolamine conjugate levels that suggest less autophagosome formation [10]. This adds to the understanding of NF-kB signalling in other conditions associated with atrophy, including unloading of the limbs through immobilization [11] and the diaphragm with controlled mechanical ventilation [12]. Moreover, autophagy has been described as a beneficial adaptive mechanism in ventilator-induced diaphragm dysfunction [13]. Similarly, higher autophagy in patients tolerating macronutrient deficit without parenteral nutrition for the first week of ICU admission may actually reflect better ‘housekeeping’ of degraded proteins and be associated with less weakness [14 ]. A complex interplay between autophagy and necrosis may partially explain conflicting findings as to the presence [15] or absence [8] of necrosis on vastus lateralis biopsy from ICU patients. Although iatrogenic necrosis cannot be excluded [16], necrosis was associated with macrophage infiltration [15]. While inflammation has been previously described with necrosis [4] and macrophage infiltration to occur in approximately 40% of biopsies as either isolated cells or small clustered &&
&
infiltrates [17], the relevance of M1 or M2 macrophage phenotypes is yet to be determined. On the other side of muscular protein balance, one study has reported unchanged synthesis in the first few days of illness, but a slight increase by 1 week [15]. Yet, more interesting than small alterations in the fractional synthesis rate of mixed muscle protein [15] are findings that contractile myosin heavy chain synthesis is specifically impaired [8,14 ] (Fig. 1). This is consistent with previous research [4,5], appears to be unaffected by nutritional regimen [14 ] and may be most marked in fast-twitch muscles [18]. With respect to glucose metabolism, hyperglycaemia can reduce diaphragm-specific force as demonstrated in an insulin-dependent model of diabetes [19]. Commentary on this result has drawn a parallel between hyperglycaemia and sepsisinduced diaphragm dysfunction, suggesting that chronic illnesses may enhance responses to critical illness [20]. However, blood glucose was not related to trans-diaphragmatic twitch pressures in 57 mechanically ventilated patients [21 ], consistent with a study in which abnormalities in glucose transporter type 4 (GLUT4) transport were described as more relevant than circulating glucose and intact upstream insulin signalling to Akt phosphorylation [6 ] (Fig. 1). GLUT4 translocation to the sarcolemma is a critical step in glucose uptake by skeletal muscle, and the localization of GLUT4 to perinuclear spaces was an exclusive differentiating feature between CIM and non-CIM diagnosed patients. Glucose responses, as determined by anaerobic metabolites, may also differ between endotoxic and haemorrhagic shock [22], suggesting that caution should be exerted when extrapolating findings between shock models. Another unique finding in CIM versus non-CIM patients is elevation in leg muscle serum amyloid A (SAA) proteins at day 5 [7]. SAA is an acute-phase response protein and marker for insulin resistance that appears to be produced locally by muscle in critical illness. Still, patients without CIM may have elevated SAA after more prolonged illness, suggesting accelerated changes in CIM that would still be observed in a presentation consistent with immobility. Issues with glucose signalling at the sarcolemma point to other impediments at both the myocyte membrane and with excitation contraction coupling. Starting with the motor end-plate, a rat model of acute and chronic sepsis has reported changes in nicotinic acetylcholine receptor (AChR) expression to a greater density of immature isoforms (g and a7) (Fig. 2a), similar to that observed with reduced neural input [23]. This is consistent with increased g-AChR mRNA in the vastus lateralis, but &
&
&&
&&
1363-1950 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-clinicalnutrition.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
241
Translational research in wasting diseases
degradation /~/synthesis
CATABOLISM extracellular
cytoplasm
Ca2+
IGF-1 receptor
Caplins
contraction
glucose sarcolemma
sarcomere E1 Ub Z
Z
cytoplasm
PI3K ATP
E2 Ub
E2
E3’s -MuRF-1 Ub
Akt
NF-kB
-atrogin-1 AMP
actin/myosin Ub
peptides +
ATP AMPK
26 S
Ub lysosome
Downstream LC3
pathways of
GLUT4 vesicle
protein synthesis
autophagolysosome
autophagosome
phagophore
MyHC synthesis
nucleus
FIGURE 1. Simplified schematic of the major systems for protein degradation and pathways related to both protein synthesis and glucose transport in the skeletal muscle of critically ill patients. Calpains can cleave sarcomere proteins including actin, myosin (MyHC), titin and nebulin for degradation by the ubiquitin proteasome pathway (UPP). Ubiquitin (Ub) is activated and transferred to a conjugating enzyme before muscle specific E3 ligases muscle ring finger-1 (MuRF-1) and atrogin-1 mark proteins for degradation. Poly-ubiquitin-tagged proteins are recognized by the 26S proteasome where they are unfolded and de-ubiquitinated for a net gain of adenosine triphosphate (ATP). Lysosomes are linked to the autophagy-lysosome pathway (ALP) as double membrane vesicles (autophagosomes) form around cellular constituents such as mitochondria before fusion with lysosomes where their contents are degraded. Basal autophagy is important for cell survival and recycling old or damaged organelles. Excessive autophagy induces pathological changes such as apoptosis. Nuclear factor kB (NF-kB) transcription factors mediate immunity and inflammation, and downstream signalling can promote protein degradation by the ALP and UPP. The balance between protein synthesis and degradation is regulated in part by Akt (protein kinase B). The induction of phosphoinositide 3-kinase (PI3K) and Akt phosphorylation follows upstream signalling such as through the insulingrowth factor-1 (IGF-1) receptor. Both insulin-dependent and insulin-independent [5’-adenosine monophosphate-activated protein kinase (AMPK)] pathways can influence intracellular GLUT4 transport. Adapted, in part, with permission from [4,15].
not rectus abdominus of ICU patients with abnormal spontaneous electrical activity, indicating CIM [4]. Longer channel-opening times of immature AChRs may affect membrane depolarization and other aspects of calcium signalling. For example, the sarcolemmal dihydropyridine receptor skeletal muscle isoform (DHPRa1s) receptor (skeletal muscle 242
www.co-clinicalnutrition.com
sub-type) of the transverse tubule (T-tubule) is mechanically coupled to the RyR1 Ca2þ channel on the sarcoplasmic reticulum of the skeletal muscle (Fig. 2b). The expression of both DHPRa1s and RyR1 has been reported to be reduced in the diaphragm of rats 24 h after induction of intra-peritoneal sepsis [24]. Furthermore, intra-cellular interleukin (IL)-1a Volume 18 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Myopathy with sepsis and mechanical ventilation Baldwin and Bersten
Motor neuron - trophic influences - axoplasmic transport
(a)
(b) sarcolemma γ
α7
ε
ε
ε
Ca2+
ACh receptors
DHPR α1s
(c)
RyR1 receptor Mitochondria SR ATP ROS
Ca2+
Force
T-tubule mPTP ROS + RCS carbonylated proteins degradation
FIGURE 2. Simplified schematic of pathological changes in skeletal muscle with critical illness at (a) the motor end plate by expression of immature acetylcholine receptor isoforms, (b) calcium leak from the sarcoplasmic reticulum and (c) formation of nonspecific permeability transition pores on mitochondria that open pathologically in response to conditions that include elevated calcium. Mitochondria are a significant source of reactive oxygen species that contribute to oxidative stress in critical illness and subsequent protein degradation. ACh, acetylcholine; ATP, adenosine triphosphate; DHPRa1s, dihydropyridine receptor skeletal muscle isoform; mPTP, mitochondrial permeability transition pore; RCS, reactive carbonyl species; ROS, reactive oxygen species; RyR1, ryanodine receptor skeletal muscle isoform; SR, sarcoplasmic reticulum; T-tubule, transverse tubule; g, fetal ACh receptor; a7, neuronal ACh receptor; e, adult ACh receptor.
may directly block RyR1 by stabilizing its normal Mg2þ inhibition, thereby suggesting how inflammation might unexpectedly reduce sarcoplasmic reticulum Ca2þ leak [25]. Excitation–contraction coupling has not been a focus of mechanical ventilation research, meaning that findings from diaphragm biopsy of 10 patients (mechanically ventilated 28–603 h for laparotomy/ thoracotomy) are novel [26 ]. Apart from force loss in type II fibres, they may require more calcium to generate force and Ca2þ sensitivity could be improved by a fast skeletal troponin activator. Similarly, a series of human and animal experiments suggest that abnormal resting sarcoplasmic reticulum Ca2þ leak and mechanical ventilation contractile dysfunction could be improved with a RyR1 stabilizer [27]. The intra-cellular effects of abnormal Ca2þ regulation include mitochondrial-free radical &
generation and activation of calpains; pathological opening of permeability transition pores of the inner mitochondrial membrane (Fig. 2c) has been observed in diaphragm and leg muscle of septic mice [10], and calpain-1 is elevated in leg muscle of patients by 2 weeks of ICU admission [8]. Calpain-1 can then cleave cytoskeletal proteins (Fig. 1) and particularly titin, which has recently been observed to be reduced after 2 days of mechanical ventilation in organ donors [28].
THE ROLES OF INFLAMMATION AND INACTIVITY Recently the role of inactivity as a dominant stimulus for diaphragm and limb dysfunction in the critically ill has been questioned [29–31]. While it is acknowledged that profound diaphragm
1363-1950 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-clinicalnutrition.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
243
Translational research in wasting diseases
wasting and weakness can occur with controlled mechanical ventilation in organ donors [28,32], these changes occur more rapidly than with unloading of limb muscles. Sieck and Mantilla [30] contend that inactivity per se does not result in diaphragm atrophy, and the removal of external loading without understanding the impact of motor neural activation (Fig. 2a) may affect interpretation of results. For peripheral muscle, wasting has been studied over the first week of ICU admission with ultrasound in a sample in which 49% had an admission diagnosis of sepsis [15]. Reductions in rectus femoris cross-sectional area (CSA) were greatest in patients with multiple as compared to single organ failure, which downgrades the proposed influence of inactivity as patients were effectively confined to bed. For the diaphragm, significant weakness has been demonstrated by reduced twitch pressures (
