Skeletal muscle‐specific myostatin overexpression promotes muscle oxidative capacity and fatigue resistance in transgenic mice

Abstract In addition to controlling muscle mass, myostatin may support oxidative metabolism and endurance. Loss of function through gene knockout or post‐natal blockade generally lowers muscle oxidative capacity and increases fatigability. These observations imply that myostatin activation could promote a more oxidative and less fatigable muscle phenotype. Gain‐of‐function approaches that activate myostatin in vivo, however, are largely absent. To test whether myostatin promotes oxidative metabolism in muscle, we constructed transgenic (TG) mice with myostatin ( Mstn ) gene overexpression restricted to skeletal muscle by inserting an Mstn cDNA construct under the MCK promoter to drive muscle‐specific expression of recombinant myostatin protein. On standard diet, TG had greater oxidative fibre expression, greater coupled maximal mitochondrial oxidative phosphorylation (OXPHOS), and increased in situ muscle fatigue resistance. Untargeted metabolomics identified greater stored carbohydrate and glycolytic intermediates in TG muscle, lower lactate/pyruvate and lower AMP that together indicate TG muscle to be energetically primed for carbohydrate‐fuelled OXPHOS. Further, TG had enhanced synthesis of spermidine, a polyamine and autophagy inducer implicated in mitochondrial quality control and geroprotection, and large changes in polyunsaturated fatty acid composition with reduced long‐chain saturated fat. When challenged by lipid overload, TG displayed some features of intolerance related to glucose clearance and contractility, but also compelling signs of resilience including maintenance of mitochondrial respiratory control and running critical power. Together, these data show that myostatin is not only a regulator of skeletal muscle mass but a central mediator of diverse metabolic pathways that reinforce muscle homeostasis and organismal resilience including carbohydrate metabolism, bioactive lipids, polyamine compounds and mitochondrial respiration.