Résumé :
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Inhibition of signalling via the activin receptor IIB (ActRIIB) is considered as a therapeutic strategy for Duchenne muscular dystrophy. However, the role of ActRIIB signalling on muscle function and metabolism is not entirely understood. Myostatin knockout mouse (Mstn-/-) is the basic animal model for this therapeutic strategy, because Myostatin, the principal ligand of ActRIIB, is not expressed. These mice develop larger skeletal muscle and muscle fibres convert from oxidative towards glycolytic fibre types. This observation led to question whether loss of Myostatin affects underlying muscle energy metabolism and energy dependent muscle function. Larger muscles that develop in absence of Myostatin are stronger but fatigue extremely rapidly. Myostatin deficiency shifts muscle energy metabolism away from aerobic towards anaerobic mode as evidenced by decreased mitochondrial respiration, increased enolase activity and exercise induced lactate acidosis. The hypermuscular state of Mstn-/- mice increases oxygen consumption, however, mice fail during aerobic exercise causing an increased energy cost of running. In conclusion, Myostatin endows skeletal muscle with high oxidative metabolism and low fatigability, thus optimising the delicate balance between muscle mass and force, exercise dependent energy expenditure and endurance capacity.The second part of this presentation addresses the effect of activin receptor blockade in the DMD mouse model mdx using soluble ActRIIB-Fc. Treatment of non-dystrophic mice with ActRIIB-Fc strongly stimulates muscle growth (55% increase) and strongly increases tetanic force (35% increase). However, treatment of mdx mice with ActRIIB-Fc only moderately stimulates muscle growth (19% increase) with no effect on tetanic force. Differently to ActRIIB-Fc, restoration of dystrophin expression using AAV-U7 mediated exon skipping increases specific tetanic force and strongly ameliorates muscle resistance to eccentric contractions. This demonstrates the rapid functional improvement of mdx muscle following dystrophin restoration. When AAV-U7 is combined with ActRIIB-Fc, muscle mass increases moderately (14%). However, combined treatment has no additional positive effect on muscle function. In fact, the positive effect of dystrophin restoration on muscle specific forces is lost when combined with ActRIIB-Fc. These data will be discussed with respect to recently published results by other groups.
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