Key considerations for investigating and interpreting autophagy in skeletal muscle.

ABSTRACT

Skeletal muscle plays a crucial role in generating force to facilitate movement. Skeletal muscle is a heterogenous tissue composed of diverse fibers with distinct contractile and metabolic profiles. The intricate classification of skeletal muscle fibers exists on a continuum ranging from type I (slow-twitch, oxidative) to type II (fast-twitch, glycolytic). The heterogenous distribution and characteristics of fibers within and between skeletal muscles profoundly influences cellular signaling; however, this has not been broadly discussed as it relates to macroautophagy/autophagy. The growing interest in skeletal muscle autophagy research underscores the necessity of comprehending the interplay between autophagic responses among skeletal muscles and fibers with different contractile properties, metabolic profiles, and other related signaling processes. We recommend approaching the interpretation of autophagy findings with careful consideration for two key reasons 1) the distinct behaviors and responses of different skeletal muscles or fibers to various perturbations, and 2) the potential impact of alterations in skeletal muscle fiber type or metabolic profile on observed autophagic outcomes. This review provides an overview of the autophagic profile and response in skeletal muscles/fibers of different types and metabolic profiles. Further, this review discusses autophagic findings in various conditions and diseases that may differentially affect skeletal muscle. Finally, we provide key points of consideration to better enable researchers to fine-tune the design and interpretation of skeletal muscle autophagy experiments.Abbreviation AKT1 AKT serine/threonine kinase 1; AMPK AMP-activated protein kinase; ATG autophagy related; ATG4 autophagy related 4 cysteine peptidase; ATG5 autophagy related 5; ATG7 autophagy related 7; ATG12 autophagy related 12; BECN1 beclin 1; BNIP3 BCL2 interacting protein 3; CKD chronic kidney disease; COPD chronic obstructive pulmonary disease; CS citrate synthase; DIA diaphragm; EDL extensor digitorum longus; FOXO3/FOXO3A forkhead box O3; GAS; gastrocnemius; GP gastrocnemius-plantaris complex; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MAPK mitogen-activated protein kinase; MYH myosin heavy chain; PINK1 PTEN induced kinase 1; PLANT plantaris; PRKN parkin RBR E3 ubiquitin protein ligase; QUAD quadriceps; RA rectus abdominis; RG red gastrocnemius; RQ red quadriceps; SOL soleus; SQSTM1 sequestosome 1; TA tibialis anterior; WG white gastrocnemius; WQ white quadriceps; WVL white vastus lateralis; VL vastus lateralis; ULK1 unc-51 like autophagy activating kinase 1.