The Vicious Cycle of Myostatin Signaling in Sarcopenic Obesity: Myostatin Role in Skeletal Muscle Growth, Insulin Signaling and Implications for Clinical Trials.

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.

A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals.

CONTEXT: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. OBJECTIVE: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). DESIGN AND SETTING: A 5-d prospective study conducted in the research unit of an academic center. PARTICIPANTS: Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m(2)), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m(2)) males and females, between ages 18 and 30. INTERVENTION: Participants were studied before and after a 5-d HFD (65% fat). MAIN OUTCOME MEASURES: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. RESULTS: Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. CONCLUSIONS: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

Plasma protein carbonyl response to increasing exercise duration in aerobically trained men and women.

The purpose of this study was to determine the effect of aerobic exercise duration on plasma protein carbonyl concentrations, a marker of protein oxidation, in aerobically trained men and women. Eight men (age: 27 +/- 4 years, VO (2peak): 4.09 +/- 0.26 L x min (-1); mean +/- SD) and 7 women (age: 27 +/- 6 years, VO (2peak): 2.33 +/- 0.24 L x min (-1)) exercised on an electrically-braked cycle ergometer at 70 % VO (2peak) for 30, 60 or 120 minutes on three separate days. Plasma samples collected before and immediately, 30- and 60-minutes post-exercise were analyzed for protein carbonyls. Mean oxygen uptake was greater for men in all conditions (2.75 +/- 0.03 L x min (-1); 38 +/- 0.43 ml x kg (-1) x min (-1)) compared to women (1.57 +/- 0.03 L x min (-1); 24.1 +/- 0.47 ml x kg (-1) x min (-1)). Total work performed during the exercise sessions was also greater for men than for women during the 30 (368 +/- 11 versus 223 +/- 7 kJ), 60 (697 +/- 17 versus 423 +/- 18 kJ), and 120-minute conditions (1173 +/- 44 versus 726 +/- 28 kJ) (Mean +/- SEM). Although these comparisons were significant (p < 0.0001), sex differences in total work performed and mean VO (2) did not result in sex differences in protein carbonyls. However, a condition by time interaction was observed with greater post-exercise values following the 120-minute condition compared to both the 30- and 60-minute conditions. Protein carbonyl concentration was greatest immediately post-exercise for both men and women and generally declined in a linear trend through one hour of recovery. These data suggest that protein carbonyl concentration is elevated by cycling exercise performed at 70 % VO (2peak), is greater following longer duration rides, begins to recover within one hour following exercise, and is not different between men and women.

Hormone responses to resistance vs. endurance exercise in premenopausal females.

Sixteen, cross-trained, premenopausal women participated in an endurance, resistance, and control session to compare hormone responses. The resistance session included 3 sets of eight exercises at 10 RM intensity. The endurance session consisted of a 40-min cycling protocol at 75% of maximal heart rate. During the control session, subjects rested for 35 min. Serum DHEA, estradiol, testosterone, growth hormone, IGF-I, cortisol, and plasma lactate concentrations were measured pre-exercise, post-exercise, and 30 min into recovery. Differences in intensity variables existed between the three sessions. Endurance exercise elicited increases in growth hormone, estradiol, and testosterone compared to the control session, and growth hormone increased after the resistance compared to the control session. The exercise protocols used in this study indicate that an acute bout of exercise can stimulate the endocrine system in premenopausal females. In addition, these results indicate that differences exist between these two exercise protocols when compared to a control session.