The Regulatory Role of Myostatin on Skeletal Muscle Metabolism and Fatigue Resistance

Rationale Myostatin (Mstn) is a key regulator of muscle mass during development, but its regulatory role remains unclear in adulthood. Recently, Mstn inhibition in adult mice resulted in reduced muscle oxidative capacity and reduced exercise tolerance, implicating a role for Mstn in metabolic control. To explore this, Mstn overexpressing transgenic (TG), knock‐out (KO) and wild‐type (WT) mice (3 months old, n=7–10/group) were exposed to regular, high‐fat, low carbohydrate or high carbohydrate diet (RG, HF, LC, HC) for 4 weeks prior to assessment of body composition, exercise tolerance and muscle function. Methods Body composition was assessed by MRI. Exercise tolerance was assessed by treadmill endurance using 3–4 constant speed tests to establish critical power (CP, related to aerobic capacity) and the power‐duration curvature constant (W′, related to anaerobic work). Muscle fatigue index (% reduction in peak tension at 1 min) was measured in the gastrocnemius‐soleus‐plantaris complex using an incremental stimulation protocol in situ (10V, 70Hz, 15×0.5ms tetanic trains, with 1 min at each of 15, 30, 60, and 120 trains/min). Data were analyzed by two‐way ANOVA (diet × genotype). Results There were main effects of diet and genotype, and a significant diet × genotype interaction, on body mass and composition. Across all diets, KO animals were heavier (37±3 g) and leaner (6±4% fat mass) compared with TG (27±5 g, 13±11%) or WT (28±6 g, 14±11%). In HC and HF diet, fat mass was significantly lower in KO (6±1% and 10±4%, respectively) compared with TG (10±3%, 31±4%) or WT (12±2%, 32±5%). There was no main effect of diet on exercise tolerance (CP or W′ normalized to lean body mass), but there was a significant main effect of genotype. CP and W′ were significantly lower in KO (1.5±0.2 mW/g, 1.3±0.5 mJ/g) compared with TG (2.1±0.3 mW/g, 1.8±0.6 mJ/g) or WT (2.3±0.2 mW/g, 2.0±1.0 mJ/g). A diet × genotype interaction revealed that CP was significantly greater in TG following a HF diet (2.3±0.4 mW/g) compared with all other diets (2.0±0.2 mW/g). As expected, gastrocnemius mass and peak force was significantly greater in KO (330±65 mg, 466±183 mN) compared with TG (159±15 mg, 430±154 mN) or WT (167±17 mg, 394±134 mN). An interaction showed that fatigue was lowest in WT‐HF and greatest in KO‐LC: overall, fatigue was significantly lower in TG (53±9 % at 120 trains/min) compared with KO (62±12 %) or WT (57±15 %) at all but the lowest intensity. Conclusions Mstn KO mice have a larger, leaner phenotype, with ~30% greater lean body mass than WT or TG. However, KO muscle was more fatigable and, when normalized to lean body mass, was associated with a reduced endurance running performance. In contrast, lean body mass in Mstn overexpressing TG was not different from WT, both showing fat mass increase in HC and HF diets. However, TG had greater fatigue resistance to stimulated contractions and indices of running endurance, indicative of greater oxidative energy provision. These results support the hypothesis that Mstn has an essential regulatory function on skeletal muscle metabolism in adulthood, and the molecular pathways involved deserve further study. Support or Funding Information Supported by NIH/NIGMS SC1GM089648