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Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

Endocrine alterations from concentric vs. eccentric muscle actions: A brief review Robert R. Kraemer a,⁎, V. Daniel Castracane b a b

Deparment of Kinesiology and Health Studies, Southeastern Louisiana University, Hammond, LA, 70402 Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, 701 W. 5th St. Odessa, TX, 79763

A R T I C LE I N FO

AB S T R A C T

Article history:

Resistance exercise has a positive effect on many tissues, including heart, bone, skeletal muscle,

Received 23 July 2014

and nervous tissue. Eccentric muscle actions offer a unique and a potentially beneficial form of

Accepted 23 October 2014

exercise for maintaining and improving health. During resistance exercise, the effects of gravity,

Keywords:

greater muscle load during an eccentric (lengthening) muscle contraction than a concentric

Eccentric

(shortening) muscle contraction. Consequently, older patients, patients with muscle or limb

Growth hormone

movement limitations or injuries, as well as cancer patients may be able to benefit from isolated

Testosterone

eccentric muscle actions. There are specific physiological responses to eccentric muscle

Insulin

contractions. This review will describe the effects of different eccentric muscle contraction

Cortisol

protocols on endocrine responses that could have positive effects on different tissues and

and mechanical properties of the sarcomere and connective tissue in skeletal muscle allow a

recommend direction for future research. © 2015 Elsevier Inc. All rights reserved.

The latter half of the 20th century brought a number of published studies on the physiology of resistance exercise; however, since the turn of the 21st century, there has been a sharp increase in the number of scientific articles devoted to investigating the effects of resistance exercise. Much of this is likely due to the realization of benefits of resistance training that is now recommended for the prevention and rehabilitation of disease and musculoskeletal injury [1–5]. Resistance exercise is known to have positive health effects on numerous tissues including heart [6], bone [7], skeletal muscle [8] and corticospinal [9] as well as hippocampal [10] nervous tissue. Lifting a weight during dynamic resistance exercise necessitates force production during muscle shortening (concentric contraction) whereas lowering a weight (eccentric contraction) requires force production during muscle lengthening (see Supplementary Fig. 1) [11]. Resistance training is

usually performed with CON and ECC contractions at the same, constant load. Due to effects of gravity and connective tissue properties, an individual can complete an eccentric [ECC] muscle contraction with a greater load than can be lifted using a concentric [CON] contraction [12,13]. As such, fewer motor units are recruited during ECC contractions compared with equally loaded CON contractions [14], which is attributed to the greater economical generation of tension during ECC muscle actions [14]. Moreover, the lower motor unit recruitment during ECC contractions reduces metabolic requirements compared to CON contractions, resulting in less sympathetic activation and blood lactate levels with equally loaded ECC muscle actions [15,16]. Consequently, older patients [17], patients with muscle or limb movement limitations or injuries [17,18], as well as cancer patients [19] may benefit from isolated eccentric muscle actions. Thus,

Abbreviations: ECC, eccentric; CON, concentric; GH, growth hormone; IGF-I, insulin-like-growth-factor I; LVH, left ventricular hypertrophy; 1-RM, one-repetition maximum; P13K-Akt/mTOR, phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin; IAPP, islet amyloid polypeptide; Fstl3, follistatin-like 3; BMI, body mass index. ⁎ Corresponding author at: Department of Kinesiology and Health Studies, Southeastern Louisiana University, Hammond, LA 70402. E-mail address: [email protected] (R.R. Kraemer). http://dx.doi.org/10.1016/j.metabol.2014.10.024 0026-0495/© 2015 Elsevier Inc. All rights reserved.

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eccentric muscle actions offer a unique and a potentially beneficial form of exercise for maintaining and improving health [17,18]. Since 1995, there has been a very sharp increase in the number of scientific investigations involving ECC muscle contractions (see Supplementary Fig. 2A) which have been increasingly cited in the scientific literature (see Supplementary Fig. 2B). An additional aspect to consider is that eccentric muscle contractions in an untrained state are typically associated with greater inducement of muscle injury than concentric contractions against the same load [20], thus, eccentric exercise regimens must be modified for the individual to maximize benefit, enhance adherence, and minimize injuries. However, one bout of eccentric [21] or isometric [22] muscle contractions has been shown to elicit a protective effect from subsequent eccentric-contraction-induced muscle injury. There are specific physiological responses and adaptations to ECC muscle actions on different tissues and organ systems that have been reported. They include cardiovascular [23,24], respiratory [23], neuromuscular [e.g. 25,26], endocrine [e.g. 12,27], bone [28], connective tissue [29], inflammatory [30,31], and oxidative stress [32,33] responses. Conducting initial research in this area necessitated that our lab designs and builds our own specific equipment; however, exercise machines that isolate or enhance ECC muscle actions have since been developed for commercial use [34,35] and are now found in fitness centers. Differences in physiological effects of these different forms of muscle contraction, particularly endocrine changes, have the potential to enhance muscle growth and improve insulin sensitivity, and have been the focus of studies in this area. In this review we will discuss what is known regarding different endocrine responses and adaptations to concentric and eccentric exercise. Specifically, the review will focus on studies that have investigated anabolic (growth hormone, testosterone, free testosterone, IGF-1) and glucoregulatory (insulin, C-peptide, amylin, cortisol, ghrelin) hormone responses and adaptations to ECC muscle actions compared with CON muscle actions. These endocrine responses to ECC and CON muscle actions are also affected by other factors including, gender [e.g. 36] and training status [e.g. 37]. Moreover, these endocrine responses and adaptations to ECC and CON muscle actions can be affected by factors including resistance exercise muscle groups (lower and upper body) [e.g. 38], load/volume [e.g. 39], time-under tension [e.g. 40,41], and rest-period intervals between sets [e.g. 42], gender [e.g. 43], and age [e.g. 44]. The muscle groups and muscle loads have varied among different studies; however, a consistent pattern of hormone response can be observed among these different research designs. The following review will describe the effects of eccentric exercise on different endocrine responses and suggest direction for future research.

1. Growth hormone, insulin-like growth factor-1, and testosterone Growth hormone (GH), insulin-like growth factor I (IGF-I), and testosterone are known to have an important anabolic effect on protein synthesis and maintenance or improvement of

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muscle mass is particularly important for moderate and older populations at risk for loss of muscle mass. A review of all the possible mechanisms for the effect of circulating GH, IGF-I, and testosterone on protein synthesis is beyond the scope of this paper, but has been reviewed elsewhere [45,46]. However, some important signaling mechanisms will be mentioned. It has been shown that disrupting the phosphatidylinositol 3kinase-protein kinase B-mammalian target of rapamycin (P13K-Akt/mTOR) pathway will induce sarcopenia [47] and androgen withdrawal reduces myofibrillar protein synthesis via Akt/mTORC1 signaling in myotubes [48]. Treatment of myotubes with testosterone will activate mTOR signaling independent of Akt [48]. There is also evidence for a role of IGF-I isoforms to facilitate muscle hypertrophy to stimulate fusion of satellite cells in muscle fibers to increase the DNAto-protein ratios in order to facilitate greater protein synthesis [49,50]. In addition to its effect on stimulating circulating IGF-I isoforms, GH has been shown to play an important role in substrate FFA delivery to muscle [51]. Several studies have determined growth hormone (GH), insulin-like growth factor I (IGF-I), and testosterone responses to ECC and CON muscle actions (Table 1). Durand et al. [27] compared GH, testosterone, and free testosterone responses to two trials, one using CON muscle actions and the other using ECC muscle actions. Ten young men completed a resistance exercise protocol that consisted of 4 sets/12 repetitions (muscle actions per set)/90 s of rest in between sets (90 s rest) at 80% of a CON 10-repetition maximum load. GH, testosterone, and free testosterone increased for both CON and ECC trials; however, GH responses were greater in the CON trial. The authors indicated that ECC contractions concluded that the greater GH responses were likely due to greater relative workload for the CON trial, since the same load was used for CON and ECC trials; however, testosterone and free testosterone increased the same in both trials. In a follow-up study, RR Kraemer et al. [12] conducted a study in which young men completed separate CON and ECC resistance exercise protocols and performed 4 sets/10 repetitions/90 s rest at 65% of a CON 1-repetition maximum in the CON trial and 65% of an ECC 1-repetition maximum in the ECC trial. GH increased similarly in both trials, as did free testosterone. Total testosterone did not increase significantly in response to this moderately loaded protocol. The investigators concluded that loading CON and ECC muscle contractions relative to their maximal contraction produces similar GH, testosterone, and free testosterone responses. Goto et al. [40] conducted 4 trials with 9 male subjects that included leg extension exercise in which loading and time of contraction were altered. The trials included: 1) low intensity, slow CON (5 s)/fast ECC (1 s) contractions; 2) low intensity, slow ECC (5 s)/fast CON (1 s) contractions; 3) low intensity, slow CON (3 s)/slow ECC (3 s) contractions; and 4) high intensity, fast CON (1 s)/fast ECC (1 s) contractions. The low load was 50% of one-repetition maximum and the high load was 80% of one repetition maximum. The low load slow CON (1), slow ECC (2), and slow CON/slow ECC (3) all stimulated an increase in GH similarly, whereas (4) high load fast CON/fast ECC did not stimulate a GH response. The responses of testosterone were different from GH responses in that all protocols stimulated a similar increase in testosterone. The

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Table 1 – Studies that have determined the effects of eccentric and concentric muscle actions on endocrine reponses in humans. Study

Year Subjects

Study design

Growth hormone (GH), insulin-like growth factor-1 (IGF-I), and total and free testosterone (TT, FT) Durand 2003 10 young recreationallyCON and ECC trials: 4 sets/12 reps/90 s et al. [27] trained men between sets (90 s rest) at 80% of a CON 10-repetition maximum load. RR Kraemer 2006 7 young recreationally4 sets/10 reps/90 s rest at 65% of a et al. [12] trained men CON 1-RM in CON trial and 65% of ECC 1-RM ECC trial Goto et al. [40] 2009 9 untrained young men 4 trials: 1) low intensity, slow CON (5 s)/fast ECC (1 s); 2) low intensity, slow ECC (5 s)/fast CON (1 s); 3) low intensity, slow CON (3 s)/slow ECC (3 s); 4) high intensity, fast CON (1 s)/fast ECC (1 s). Low load = 50% 1-RM; high load = 80% 1-RM. Libardi et al. [52] 2013 17 untrained young women 5 sets of maximal ECC slow range of motion (30°/s) isokinetic contractions vs. fast range of motion (210°/s) ECC isokinetic contractions Yarrow et al. [53] 2007 22 young, untrained men 2 trials: 1) 4 sets/6 reps/6 s per rep/1-min rest between sets of bench press and squat exercises at 52.5% of 1-RM, 2) 3 sets/6 reps/6 s per rep/1 min rest between sets – CON at 40% CON 1-RM; ECC at 100% CON 1-RM Yarrow et al. [54] 2008 22 untrained men Completed 5 wk of bench press and squat training, either traditional 4 sets/6 reps at 52.5% 1-RM or ECC + training of 3 sets of 6 repetitions at 40% 1 RM concentric and 100% 1 RM eccentric Zebrowska 2013 18 resistance-trained male Completed 2 min of arm crank et al. [55] athletes with (9) and without exercise on different randomized (9) left ventricular hypertrophy occasions using CON contractions and 10 untrained controls and the other using ECC contractions. WJ Kraemer 2001 32 young men 4 training groups that completed et al. [56] 19 wk of leg extension exercise training using 1) only CON muscle actions, 2) CON and ECC muscle actions (CON/ECC), 3) double CON (CON/CON) muscle actions for each repetition, 4) no exercise. After 19 wks of training, hormone responses were determined for CON test and ECC test. Ojasto and 2009 11 active young men CON/ECC exercise under 4 conditions: Hakkinen [57] using 70%, 80%, 90% and 100% 1-RM ECC load for four different conditions and 70% 1-RM for the CON load under all conditions. Carruso et al. [58] 2010 14 young men and 3 groups: 1) 6 sets/10 reps of flywheel 14 young women activity for CON 2) 3 sets/10 reps of flywheel activity CON + ECC actions, with equal total work for groups 1 and 2. 3) 3 sets of CON only with approximately half the total work.

Insulin, C-peptide, and amylin Krishnan et al. [59] 1998 8 young and 8 older sedentary males

10 sets of 10 reps of ECC bench press and leg extension exercises at a CON-three-repetition-maximum load at 3 s per contraction and reduced weight as subjects could not maintain contraction speed.

Findings ↑ GH, T, FT in both trials but greater ↑ GH in CON trial Similar ↑ GH and ↑ FT in both trials; no change in TT. Trials 1, 2, and 3 all ↑ GH the same; no GH change in trial 4. All 4 trials ↑ TT similarly.

Slow maximal ECC isokinetic contractions elicited greater post and 15 min post-exercise GH responses; no change in TT. Similar ↑ GH and FT for both trials. No change in TT

Pre- and post-training ↑ GH, ↑ TT and ↑ FT responses to traditional and ECC + exercise were similar.

ECC exercise elicited an enhanced IGF-I response in athletes with LVH.

↑ GH responses to CON test were greater in the CON and CON–CON trained groups. Responses to ECC test were greater for the CON/ECC trained group.

A non-significant trend for greater GH response to 90% ECC/70% CON muscle actions compared with 70% ECC/70% CON Greater ↑ GH in women than men for 6 sets of CON and 3 sets of CON at both one min and 30 min after exercise. For both genders, 3 sets of CON + ECC → smaller 1-min postexercise GH responses than 6 sets of CON only exercise, but greater GH responses at 30 min post exercise.

Area-under-the-curve (AUC) glucose disposal rate not different between young, older, and control groups. Greater ↑ C-peptide (and thus β-cell) response to hyperglycemia in the younger vs. older subjects.

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Table 1 (continued) Study

Year Subjects

Study design

Findings

Cook et al. [60]

2014

10 active young men

AUC glucose and insulin similar for CON and ECC trials.

Miles et al. [61]

2010

12 men and women

RR Kraemer et al. [11]

2004

9 young, recreationally active men

Green et al. [62]

2010

10 young women

3 trials: oral glucose tolerance test after 1) level running (CON), 2) downhill running (ECC) matched for metabolic rate, and 3) control 6 sets/10 eccentric reps of elbow flexors and extensors to damage muscle, followed by a high carbohydrate/low fat diet or low carbohydrate high fat and protein diet for the first 8 h after exercise 2 trials: 1) CON only and 2) ECC only muscle actions. 4 sets/12 repetitions/90 s between sets bench press, leg extension, military press, and leg curl exercises performed at 80% of a 10-RM load. Two bouts of downhill running separated by 48 h. OGTT after each bout.

Kirwan et al. [63]

1992

6 young untrained males and females (3/3)

2 bouts: 1) downhill running (ECC) and 2) cycling (CON)

Cortisol and ghrelin Smith et al. [64] 1989

8 young men

Kirwan et al. [63]

1992

6 healthy individuals

Gilles et al. [65]

2006

28 young women with resistance exercise experience

Hollander et al. [24]

2003

8 young men with resistance exercise experience

RR Kraemer et al. [11]

2004

9 young, recreationally active men

Goto et al. [40]

2009

9 untrained young men

2 bouts: 1) downhill jogging (ECC) and 2) uphill running (CON) 2 bouts: 1) downhill running (ECC) and 2) cycling (CON) 2 groups, 9 weeks of training: 1) 6 s CON contractions and 2 s ECC contractions for 4 different exercises at 6-8 RM loads. 2) Same training except 2 s CON and 6 s ECC contractions. 4 sets/12 repetitions/90 s rest of bench press, leg extension, military press, and leg curl exercises performed using an 80% CON 1-RM load 2 trials: 1) CON only and 2) ECC only muscle actions. 4 sets/12 repetitions/90 s between sets bench press, leg extension, military press, and leg curl exercises performed at 80% of a 10-RM load 4 trials: 1) low intensity, slow CON (5 s)/fast ECC (1 s); 2) low intensity, slow ECC (5 s)/fast CON (1 s); 3) low intensity, slow CON (3 s)/slow ECC (3 s); 4) high intensity, fast CON (1 s)/fast ECC (1 s). Low load = 50% 1-RM; high load = 80% 1-RM.

findings suggest the importance of time under tension for both CON and ECC muscle actions against the same low absolute load to elicit a GH response and suggests that high load with less timeunder-tension is less effective in stimulation of GH. However, testosterone responds similarly to both muscle actions against the same low absolute load and to the high load with less timeunder-tension. Thus, in order to elicit GH as well as testosterone responses, slower muscle contraction with longer time-undertension appears to be more effective. Recently, Libardi et al. [52] compared the effects of 5 sets of maximal slow range of motion (30°/s) vs. fast range of motion

Insulin ↑ more one day after the damaging exercise from high carbohydrate/low fat diet compared with high fat/high protein diet.

Similar ↑ glucose and insulin concentrations increased postexercise for both CON and ECC trials. No change in C-peptide or amylin. The OGTT 48 h following the first ECC bout → greater ↑ insulin and ↑ glucose and insulin responses than from the OGTT 48 h after the second ECC bout. Impaired glucose uptake from downhill running but not cycling

↓cortisol similarly for both trials No change in cortisol for either bout Elevated 24 h urinary cortisol concentrations in the extended CON time under tension but not extended ECC time under tension. Cortisol declined post-exercise in both trials but was reduced more after the ECC trial than the CON trial. Ghrelin decreased significantly in the CON trial, not the ECC trial and was correlated with elevation of GH concentrations

↑ cortisol only with 5 s of CON contraction at 50% 1-repetition maximum

(210°/s) ECC isokinetic contractions on GH and testosterone in untrained women. The slow maximal ECC isokinetic contractions elicited greater post and 15 min post-exercise GH responses, whereas testosterone and free testosterone did not change significantly. In another investigation, Yarrow et al. [53] compared GH, testosterone and free testosterone responses in 22 untrained men to resistance exercise using a traditional protocol and an ECC load-enhanced protocol. Subjects completed 4 sets/6 repetitions/6 s per rep, with 1-min rest between sets of bench press and squat exercises at 52.5% of a 1-RM absolute

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load. Then subjects were randomly assigned to perform a subsequent bout of the traditional protocol they had performed or an ECC enhanced protocol. The ECC load-enhanced protocol consisted of 3 (rather than 4) sets/6 repetitions/6 s per rep, with 1 min rest between sets, however, the CON muscle action was performed with a 40% 1-RM of CON contraction load and the ECC muscle action was performed with a 100% 1-RM of CON contraction load. Comparing the second trial, GH increased significantly following the ECC load-enhanced as well as the traditional protocol. Although the mean percent change in GH between the two trials was considerably greater in the ECC load-enhanced trial, variability in responses resulted in no significant difference between groups. Similar responses were observed after both protocols for free testosterone, but total testosterone did not change. The investigators concluded that both protocols elicited similar changes in GH and testosterone. In a follow-up study the same principal investigator compared the 5-wk training effects of the same ECC loadenhanced protocol to the traditional protocol in young men [54]. They concluded that the two training protocols resulted in similar post-exercise increases in testosterone, free testosterone, and GH (app. 13%, 21%, and 750–1200%, respectively), as well as similar increases in muscular strength adaptations. Focusing on two different athletic populations, Zebrowska et al. [55] determined the acute effects of ECC and CON exercises on GH, testosterone, and IGF-1 in trained male athletes with and without left ventricular hypertrophy. Left ventricular hypertrophy (LVH) is a healthy adaptation in endurance athletes to volume load on the heart [66,67]. Exercise consisted of two minutes of arm crank exercise on different randomized occasions, one using CON contractions and the other using ECC contractions. ECC exercise resulted in an enhanced response of IGF-I in athletes with LVH leading authors to conclude that IGF-I released from skeletal muscle (one of the sources of IGF-1 in addition to live) may contribute to LVH. WJ Kraemer et al. [56] investigated the effects of different forms of training of 32 men on GH responses. Subjects were assigned to training groups that completed leg extension exercise using only CON muscle actions, CON and ECC muscle actions (CON/ECC), double CON (CON/CON) muscle actions for each repetition, or no exercise. After 19 wk of training, subjects were tested for hormone responses to different muscle actions. On the first post-training day they completed 3 sets of 30 isokinetic CON muscle actions and the following day they completed the same test for ECC muscle actions. GH responses to the CON test were greater in the CON and CON– CON trained groups (specificity effect). GH responses to the ECC test were greater for the CON/ECC trained group. The investigators concluded that GH responses are responsive to the form of muscle action. Ojasto and Hakkinen [57] compared the adjusted loads of ECC muscle actions for 4 sets/10 repetitions/2 min rest of bench press exercise. Moderately young male subjects completed the CON/ECC exercise under 4 conditions: using 70%, 80%, 90% and 100% 1-RM ECC load for four different conditions and 70% 1-RM for the CON load under all conditions. The authors reported a trend for greater GH response to 90% ECC/70% CON muscle actions compared

with 70% ECC/70% CON; however, the differences were not significant. The investigators suggested that these responses to enhanced ECC loading appeared to be more favorable for muscle hypertrophy. Finally, Carruso et al. [58] used a flywheel device to determine anabolic hormone responses to male and females subjects performing 6 sets/10 reps of flywheel activity for CON or 3 sets/10 reps of flywheel activity CON + ECC actions, with equal total work performed for both groups. A third group performed 3 sets of CON only with approximately half the total work. GH responses were greater in women than men for 6 sets of CON and 3 sets of CON both one min and 30 min after exercise. For both genders, 3 sets of CON + ECC elicited smaller 1-min post-exercise GH responses than 6 sets of CON only exercise, but greater GH responses at 30 min post exercise, suggesting a delayed response for the ECC muscle actions. For testosterone responses, as expected, all 3 protocols elicited greater testosterone responses in men than women. Moreover, the 6 sets of CON and 3 sets of CON + ECC elicited greater testosterone responses than 3 sets of CON. Collectively, these studies suggest that ECC exercise will elicit similar GH, IGF-I, and testosterone responses when loaded for specific CON 1-RM or ECC 1-RM (see Fig. 1). Typically, CON and ECC muscle actions are performed with the same muscle load (wt.) and under those conditions, ECC muscle contractions will elicit significant but lower GH responses than CON muscle actions, since GH responses appear to be more sensitive to loading of ECC contractions than are IGF-I and testosterone. There is some evidence that increasing time-under-tension for isolated ECC muscle actions will enhance the increase in GH, but not IGF-I and testosterone responses. There is also evidence that increasing total muscle work by adding ECC contractions to CON contractions or increasing number of CON contractions will increase testosterone responses in men. Resistance exercise training is known to result in increased GH and testosterone concentrations in young and middle-aged men [68] and increases GH in women [69], thus using ECC resistance exercise in older populations should be considered as an important medical treatment option. The significant increases in GH, IGF-I and testosterone induced by ECC muscle actions with moderate loading can be used to elicit anabolic hormone responses that are expected to lead to improved muscle mass in the aging population, at risk for sarcopenia [46].

2.

Insulin, C-peptide, and amylin

The effects of ECC exercise on pancreatic islet cell hormone responses and insulin sensitivity are of particular interest due to the increased prevalence of type II diabetes in the United States [70]. Pancreatic hormones are key to maintaining proper glucose delivery to tissues. The mechanisms for insulin secretion by β-cells in the pancreas and translocation action of glucose transporters produced in response to insulin binding to an α-subunit of a heterotrimeric tyrosine kinase transmembrane receptor in skeletal muscle have been well reviewed elsewhere [71]. C-peptide is a product of proinsulin cleavage and was thought to be inert and thus mainly used as

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Fig. 1 – Summary of effects of eccentric (ECC) compared to concentric (CON) muscle contractions with different loading on endocrine responses.

a marker for insulin release [72]. However, recent evidence indicates that C-peptide is a bioactive peptide that may play a role in protecting hyperglycemia-induced epithelial cell apoptosis through inhibition of protein kinase C- and NADPH oxidase-dependent intracellular ROS production as well as through elimination of hyperglycemia-induced transglutaminase 2 generation [73]. Amylin (also known as islet amyloid polypeptide, IAPP) is co-secreted from pancreatic β-cells with insulin in response to glucose [74,75] because they share a common regulatory promoter motif [76,77]. Amylin regulates blood glucose by reducing gastric emptying and inhibiting hepatic glycogenolysis [74]. There is evidence that acute ECC muscle actions affect these glucoregulatory hormones. Of early interest was the possible enhanced effect of ECC exercise on acute muscle damage and temporary insulin resistance due to evidence of possible damage-induced reduction of glucose disposal rate [59,78]. Krishnan et al. used a resistance protocol designed to produce muscle damage. Male subjects completed isolated ECC muscle contractions (lowering weight) of bench press and leg extension exercises [59]. The protocol consisted of 10 sets of 10 repetitions at a CON-three-repetition-maximum load at 3 s per contraction and reduced weight as subjects could not maintain contraction speed. Using a hyperglycemic clamp, glucose disposal rate area-under-the-curves (AUC) were not different between younger and older subjects and their control groups. However, there was a greater increase in Cpeptide (and thus β-cell) response to the hyperglycemia (via glucose infusion) in the younger vs. older subjects. In a recent study Cook et al. [60] investigated the effects of damaging ECC exercise on glucose disposal after an oral glucose

tolerance test (OGTT) and rest (control), CON focused contractions (level treadmill running), or ECC focused contractions (downhill running). Running protocols were matched for degree of metabolic stress. Area-under-the-curve glucose and insulin concentrations were similar for the CON and ECC trials. The investigators concluded that muscle damaging ECC exercise did not affect insulin and glucose tolerance to an OGTT. Miles et al. [61] used a counterbalanced-crossover design with subjects completing 6 sets of 10 eccentric repetitions of elbow flexors and extensors to damage muscle, followed by a high carbohydrate/low fat diet or low carbohydrate high fat and protein diet for the first 8 h after exercise. Insulin levels increased to a greater extent one day after the damaging exercise with the high carbohydrate/low fat diet compared with the high fat/high protein diet. The increases in β-cell response were correlated with body mass index (BMI) and waist-hip-ratio. The investigators speculated that subjects with greater visceral fat (higher BMI and waist-hip-ratio) would have been more accustomed to fatty acid flux, and thus the high fat diet would have produced less β-cell response, explaining the different insulin responses after insulin resistance from muscle damage and the effects of the two diets. In a study from our lab we compared the CON and ECCmuscle-action-induced responses of insulin, C-peptide, and amylin to those induced by CON muscle actions in 9 men [11]. Amylin is a beta-cell peptide that regulates blood glucose by inhibiting alpha-cell glucagon release and reducing gastric emptying [74]. In separate trials, nine young men completed CON and ECC muscle actions for bench press, leg extension, military press, and leg curl exercises at 80% of a 10-RM load. In both trials subjects completed 4 sets/12 repetitions/90 s between

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sets of the 4 exercises. Blood glucose and insulin concentrations increased post-exercise for both CON and ECC trials, however amylin and C-peptide concentrations did not change. The authors concluded that both forms of muscle contraction using moderate loads elicit similar increases in insulin and blood glucose without affecting amylin. In another study, Green et al. [62] investigated the effect of two different bouts of ECC exercise on glucose and insulin responses to an oral glucose tolerance test (OGTT) 48 h following the ECC exercise. Ten young women performed two bouts of downhill running separated by two weeks. The OGTT 48 h following the first ECC bout resulted in greater insulin and glucose responses than from the OGTT 48 h after the second ECC bout. The authors concluded that ECC exercise elicits protective effects resulting in subsequent ECC exercise not eliciting changes in glucose and insulin responses. Kirwan et al. [63] also used downhill running to induce muscle damage in men and women and determined relationships with cortisol and insulin sensitivity. A euglycemic– hyperinsulinemic clamp procedures revealed that glucose uptake was impaired by downhill running but not CON muscle actions from cycle ergometry (which disappeared by 48 h) suggesting that the eccentric-contraction-induced muscle damage was the cause of reduced insulin sensitivity, but there was no relationship with cortisol. Thus, existing studies suggest that isolated moderatelyloaded ECC muscle actions will increase blood glucose and insulin in a similar fashion to that of similarly loaded CON muscle contractions. However, C-peptide and amylin concentrations do not respond to this protocol (see Fig. 1). In addition, there is evidence of a protective effect of ECC exercise on glucose uptake and thus insulin responses on subsequent bouts of ECC muscle actions. Disparate data exist suggesting that 1) muscle damage produced by excessive ECC muscle contractions does not affect insulin and glucose responses to an OGTT indicating glucose tolerance, and 2) that ECC muscle actions of downhill running produce muscle damage that elicits reduced glucose uptake during a euglycemic–hyperinsulinemic clamp.

3.

Cortisol and ghrelin

Cortisol is a glucocorticoid that plays a number of important roles during and following exercise, including fatty acid mobilization [79], catabolic effects on muscle (needed for muscle remodeling), as well as immunosuppressive and anti-inflammatory actions [80,81]. There is evidence that cortisol is increased by ghrelin signaling [82]. Ghrelin is an orexigenic hormone, found in acylated and non-acylated forms, which is produced primarily in the fundus of the stomach and less in other regions of the gastrointestinal track [83]. When released in greater concentrations during fasting, ghrelin transmits a peripheral hunger signal via stimulation of the hypothalamic arcuate nucleus neurons in the hypothalamus [84] which, in turn, causes increased expression of neuropeptide Y and agouti-related peptide [85,86]. An early study investigated the effects of downhill jogging (requires eccentric contractions) on leukocytosis and changes in cortisol in 8 men [64]. Downhill jogging elicited increases in circulating white blood cell counts (primarily due to increase in neutrophils), coupled with delayed onset muscle soreness in 8

men, whereas uphill walking (more concentric muscle action) did not. Cortisol declined similarly for both trials suggesting that neutrophilia produced by the eccentric exercise was not associated with increases in cortisol. Typically, decline in cortisol over time during exercise in morning hours occurs due to circadian rhythm and is observed in moderately strenuous exercise, whereas high intensity exercise typically elicits increases in hypothalamic–pituitary–adrenal axis activity resulting in increases in cortisol responses [74,87,88]. In a study mentioned earlier, Kirwan et al. [63] induced muscle damage with downhill running and compared cortisol and glucagon responses to cycling which did not produce muscle damage. Both acute cycle ergometry (primarily concentric muscle actions) and downhill running did not produce significant changes in cortisol or glucagon. In another study, Gilles et al. [65] trained young women for 9 wk and adjusted time under tension by training one group of women using 6 s CON contractions and 2 s ECC contractions for 4 different exercises at 6–8 RM loads. The other group switched the contraction times, using 2 s CON and 6 s ECC contractions. The investigators reported elevated 24 h urinary cortisol concentrations in the extended CON time under tension but not extended ECC time under tension. In a study from our lab [24], we determined cortisol responses to separate CON and ECC muscle action trials in young men. The protocol consisted of 4 sets/12 repetitions/90 s rest of bench press, leg extension, military press, and leg curl exercises performed using an 80% CON 1-RM load. Cortisol declined postexercise in both trials but was reduced more after the ECC trial than the CON trial. Cortisol concentrations were positively related to rating of perceived exertion and to pain scale ratings. In the study from our lab mentioned earlier in which we compared the CON and ECC induced glucoregulatory hormone responses in men, we also measured ghrelin responses [11]. Ghrelin decreased significantly in the CON trial, not the ECC trial and was correlated with elevation of GH concentrations. Thus, when the same moderate absolute load is used for CON and ECC, ghrelin responses to exercise are reduced with CON but not ECC muscle actions. In another study we collaborated on and mentioned earlier, Goto et al. [40] conducted 4 trials of leg extension exercise modifying loading (50% vs. 80% 1-repetition maximum) and time of contraction (1 s vs. 5 s contraction time). Cortisol only increased with 5 s of CON contraction at 50% 1repetition maximum, suggesting that 5 s of ECC contraction at 50% of a CON 1-repetition maximum was underloaded. Thus, some evidence suggests that total ghrelin is reduced with CON muscle actions which are related to increased GH concentrations, whereas ECC muscle actions do not elicit a ghrelin response. As for cortisol, if CON and ECC muscle actions are loaded relative to a CON 1-RM, data suggest that cortisol levels will increase or decline less over time with CON muscle actions compared to ECC muscle actions (see Fig. 1).

4.

Adipokines

Adipokines are cell signaling proteins released by adipose tissue. Four of the commonly investigated adipokines are leptin, adiponectin, resistin, and visfatin. Leptin is an adipokine that

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affects satiety through leptin receptors in neurons of the arcuate, ventromedial and dorsomedial hypothalamic nuclei that are sensitive to leptin expression [89]. There are no existing studies that have examined the effects of muscle action on leptin. Adiponectin is a major adipocyte secretory protein that improves insulin sensitivity via receptor binding which leads to AMPK and PPARα signaling pathways and thus is of interest regarding treatment of type II diabetes [90]. Resistin is another adipokine that is associated with insulin resistance and is thought to cause vascular endothelial dysfunction and contributes to cardiovascular disease [91]. Visfatin is an additional adipokine that is associated with hyperlipidemia and insulin resistance [92]. There are limited data regarding the effects of ECC muscle action on adipokines. One recent study by Jamurtas et al. [93] examined the effects of 45 min of downhill running on several adipokines including adiponectin, resistin, and visfatin. Adiponectin and visfatin did not change following the ECC exercise. Resistin increased significantly in response to the exercise, but this occurred only two days afterwards. The authors concluded that even though the muscle damage of the ECC exercise produces muscle damage and reduced insulin sensitivity, it did not contribute to changes in adipokines.

5.

Conclusions

5.1.

Strengths/weaknesses of existing research

Collectively, the studies we have reviewed indicate that the form of muscle contraction can clearly affect some endocrine responses to exercise. For some hormones such as GH, ECC muscle actions will produce the same GH responses as CON exercise when the muscle loads used are relative to the maximal CON or ECC strength, respectively. Studies have effectively demonstrated that when moderate loading is the same for both muscle contraction forms, there is a greater response for GH, cortisol, and ghrelin. With other hormones, such as insulin, amylin, and cortisol, muscle action elicits similar responses using the same absolute muscle loads, however, most of the investigations of glucoregulatory hormones have used underloaded ECC contractions by loading muscle with a percentage of a CON 1-RM load, and thus represent endocrine responses to muscle actions in traditional resistance exercise settings, but not the actual effect of muscle contraction type. Another weakness of previous studies is that only male subjects have been used for most of the previous studies.

5.2.

Future directions

Given the limitations of loading ECC contractions in previous studies, more investigations are needed to determine whether existing findings regarding glucoregulatory hormone responses to different types of muscle contraction are dissimilar when ECC contractions are loaded relative to ECC strength. Extending the time under tension for specific muscle actions will enhance hormone responses, yet there is a lack of studies using experimental designs that investigate this form of endocrine stimulation. More investigations should use controlled muscle contraction research designs

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that involve extending time under tension with loading relative to ECC strength. These findings could be used to design exercise regimens that produce optimal effects for enhanced muscle mass, metabolic adaptations of skeletal muscle, as well as multiple adaptations of other tissues signaled by these endocrines. This will allow exercise medicine to be used more effectively to treat pathophysiological states. Since a majority of studies investigating effects of ECC and CON muscle actions have been conducted with the male gender, there exists a possibility that some endocrine responses to ECC and CON muscle actions will differ depending upon gender difference, especially at different stages of the menstrual cycle or in women on hormone replacement therapy [94] or oral contraceptives. It is therefore important for future studies in this area to consider gender differences. There is also evidence of ECC exercise being effective in exercise prescriptions for astronauts [95]. Moreover, there is some evidence that enhancing ECC muscle actions in subjects exposed to weeks of lower limb unloading (modeling space flight) is effective in prevention of reduced oxidative capacity and increased glycolytic enzyme activity that would occur in an antigravity environment [96]. Thus, future studies involving effects of ECC enhanced contractions on endocrine responses in antigravity environments should be considered. Finally, recent investigations of muscle tissue physiology have revealed that skeletal muscle serves as an endocrine tissue, expressing myokines (such as IL-6, BDNF, and IGF-I) that have autocrine, paracrine, or systemic effects [97–99]. Irisin is a recently discovered myokine [100] that is released in response to exercise [101–107] and has been shown to have positive effects on energy expenditure in fat tissue [108] and protein expression in muscle [108] and thus could have very beneficial effects on health [109]. There is recent evidence that irisin is inversely correlated with omentin-1, an adipokine associated with risk of heart disease [110]. Moreover there is recent evidence that irisin improves glucose and fat metabolism though activation of 5′ adenosine monophosphate-activated protein kinase (AMPK) [103]. Consequently, future investigations should examine the effects of ECC and CON muscle contractions on irisin and other myokines. Additionally, there is a recent investigation using gene electrotransfer of a plasmid construct for transfection of mouse muscle to overexpress follistatin-like 3 (Fstl3), a myostatin binding protein that inhibits actions of myostatin – a satellite cell proliferation inhibitor. The investigators reported increases in muscle mass and reductions in liver fat and overall fat in animals on a high fat diet with muscle overexpression of Fstl3[111]. Some previous evidence indicates that serum levels of myostatin and Fstl3 increase similarly after either CON or enhanced ECC loading [112] and that maximal ECC muscle action enhances expression of Fstl3; moreover this response has been shown to be enhanced in postmenopausal women on hormone replacement therapy [113]. Findings from these studies should be used to develop experiments for determining optimal loading of CON and ECC muscle actions to induce beneficial effects on these muscle proteins which could be used to target age-associated sarcopenia and improved insulin sensitivity in older men and postmenopausal women. Moreover, since evidence suggests that resistance training with reduced blood flow will enhance

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expression of Fstl3 and increase cross-sectional area of trained muscle [114], future investigations should determine whether methods that reduce heat loss in specific contracting musculature will increase expression of the protein, leading to improved body composition and metabolism.

Authors' contributions Dr. Robert R. Kraemer performed a review of the literature, designed the review, summarized and interpreted results, and drafted the manuscript. Dr. V. Daniel Castracane performed a literature review, contributed to the first draft, added articles to the review, and edited manuscript with additions and revisions.

Funding There is no funding to report and there are no conflicts of interest.

Acknowledgment We acknowledge the help of Ashley Hodnett in the preparation of Supplementary Fig. 1. We acknowledge the help of Travis Real in the preparation of Supplementary Fig. 2A and B.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.metabol.2014.10.024.

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