Skeletal muscle-specific inducible AMPK1/2 knockout mice develop muscle weakness, glycogen depletion, and fibrosis that persists during disuse atrophy

The 5' adenosine monophosphate-activated protein kinase (AMPK) is an important skeletal muscle regulator implicated as a possible therapeutic target to ameliorate the local undesired deconditioning of disuse atrophy. However, the muscle-specific role of AMPK in regulating muscle function, fibrosis, and transcriptional reprogramming during physical disuse is unknown. The purpose of this study was to determine how the absence of both catalytic subunits of AMPK in skeletal muscle influences muscle force production, collagen deposition, and the transcriptional landscape. We generated skeletal muscle-specific tamoxifen-inducible AMPK alpha 1/alpha 2 knockout (AMPK alpha(-/-)) mice that underwent 14 days of hindlimb unloading (HU) or remained ambulatory for 14 days (AMB). We found that AMPK alpha(-/-) during ambulatory conditions altered body weight and myofiber size, decreased muscle function, depleted glycogen stores and TBC1 domain family member 1 (TBC1D1) phosphorylation, increased collagen deposition, and altered transcriptional pathways. Primarily, pathways related to cellular senescence and mitochondrial biogenesis and function were influenced by the absence of AMPK alpha. The effects of AMPK alpha-/- persisted, but were not worsened, following hindlimb unloading. Together, we report that AMPK alpha is necessary to maintain skeletal muscle quality.