THE ROLE OF AMPK IN REGULATING THE DYSTROPHIN ASSOCIATED PROTEIN COMPLEX

Abstract

AMP-activated protein kinase (AMPK) is a key regulator of skeletal muscle metabolism, with downstream effects on protein expression and the ability to modify dystrophic pathology in skeletal muscle. Central to the progression of muscular dystrophy is the dystrophin-associated protein complex (DAPC), a multi-protein, spring-like structure vital for maintaining sarcolemmal integrity. Activation of AMPK modifies DAPC expression and improves sarcolemmal integrity. Muscle-specific knockout reduces utrophin levels but otherwise has little impact on the DAPC. However, the role of the catalytic AMPKα subunit in DAPC biology remains unclear. Thus, the purpose of this study was to further investigate the influence of AMPKɑ on the DAPC and expand on existing evidence supporting its role in DAPC expression. Our data demonstrate that AMPKα is not necessary for baseline expression of the DAPC but does influence skeletal muscle histology. Specifically, AMPKα mKO mice demonstrate elevated whole-muscle utrophin expression that accompanies an increase in centrally nucleated fibres, suggesting excess regeneration occurs in the absence of AMPKα. Additionally, AMPKα mKO mice demonstrate normal expression of the DAPC except for reduced sarcolemmal localization of γ-sarcoglycan. These data parallel existing results to support the idea that activation of AMPK is capable of inducing expression of DAPC proteins, but AMPK signalling is not necessary for basal DAPC expression in skeletal muscle.