T.O.7 Blockade of Myostatin/ActRIIB signalling induces skeletal muscle fatigability and exercise intolerance

Abstract

<h2>Abstract</h2> Blockade of myostatin/ActRIIB signaling has been proposed as a therapeutic strategy for Duchenne muscular dystrophy (DMD) because of its supposed stimulating effect on skeletal muscle size and function. Here we show that constitutive lack of myostatin in Mstn−/− mice resulted in increased muscle fatigability, decreased exercise performance, exercise-induced abnormal lactic acidemia and decreased mitochondrial respiration. However, Mstn−/− mice develop a fiber type disproportion towards a glycolytic muscle phenotype with less mitochondria and decreased capillary density, and these developmental abnormalities may account for the observed changes in muscle function and energy metabolism. To determine the role of myostatin/ActRIIB signaling on adult muscle physiology and metabolism, we treated adult wild type mice and mdx mice for 4months with soluble Activin IIB receptor (sActRIIB-Fc) in order to block signaling by myostatin and homologous proteins. In wild type mice, sAcRIIB-Fc strongly increased muscle size and tetanic force, whereas fatigue resistance decreased. Mice exhausted precociously during treadmill exercise and this was associated with grossly elevated serum lactate levels. Treatment of mdx mice with sActRIIB-Fc, however, resulted in largely decreased specific force. Mdx mice developed extreme exercise intolerance and exercise induced lactate acidosis. Mitochondrial enzyme activities and fiber type distribution remained unchanged, thus a primary mitochondrial deficit was unlikely the cause of the exercise failure. Importantly, capillary density of muscle strongly decreased following treatment with sActRIIB-Fc and this was associated with marked dystrophic changes. Our results suggest that myostatin optimizes muscle metabolism by adapting muscle vascularization to oxygen requirements. Blockade of myostatin/ActRIIB signaling causes a capillary-fiber mismatch especially in de- and regenerating dystrophic muscle, provoking a secondary metabolic myopathy.