Activation of autophagy by globular adiponectin is required for muscle differentiation.

Regulated autophagy is a critical component for a healthy skeletal muscle mass, such that dysregulation of the autophagic processes correlates with severe myopathies. Thus, defining the biological molecules involved in the autophagic processes within skeletal muscle is of great importance. Here we demonstrate that globular adiponectin (gAd) activates autophagy in skeletal muscle myoblasts via an AMPK-dependent mechanism. Activation of autophagy through gAd promotes myoblast survival and apoptosis inhibition during serum starvation and the gAd-activated autophagy orchestrates the myogenic properties of the hormone. Consistent with this conclusion, inhibition of gAd-activated autophagy by both a pharmacological (chloroquine) or siRNA approach greatly inhibited muscle differentiation, as demonstrated by reductions in myosin heavy chain expression and myotube formation. Further support for the role of adiponectin in autophagy comes from the skeletal muscles of adiponectin KO mice which display decreased LC3 II expression and a myopathic phenotype (heterogeneous fiber sizes, numerous central nuclei). Overall, these findings demonstrate that gAd activates autophagy in myoblasts and that gAd-activated autophagy drives the myogenic properties of this hormone.