Inhibition of the Activin Receptor Type-2B Pathway Restores Regenerative Capacity in Satellite Cell-Depleted Skeletal Muscle

Degenerative myopathies typically display a decline in satellitecells coupled with a replacement of muscle fibers by fat and fibrosis. During this pathological remodeling, satellitecells are present at lower numbers and do not display a proper regenerative function. Whether a decline in satellitecells directly contributes to disease progression or is a secondary result is unknown. In order to dissect these processes, we used a genetic model to reduce the satellitecell population by ~70-80% which leads to a nearly complete loss of regenerative potential. We observe that while no overt tissue damage is observed following satellitecell depletion, muscle fibers atrophy accompanied by changes in the stem cell nichecellular composition. Treatment of these mice with an Activin receptortype-2B (AcvR2B) pathway blocker reverses muscle fiber atrophy as expected, but also restores regenerative potential of the remaining satellitecells. These findings demonstrate that in addition to controlling fiber size, the AcvR2B pathway acts to regulate the muscle stem cell nicheproviding a more favorable environment for muscle regeneration.