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bioRxiv · 10.1101/2020.07.31.223412

Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

Nichenko, A. S.·Sorensen, J. R.·Southern, W. M.·Qualls, A. E.·Schifino, A. G.·McFaline-Figueroa, J.·Blum, J. E.·Thalacker-Mercer, A. E.·Greising, S. M.·Call, J. A.
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Abstract

The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of sarcopenia resulting in reduced contractile and metabolic function. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. We found that Ulk1 phosphorylation declines in both human and mouse muscle tissue with age, therefore the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% survival rate), muscle contractile and metabolic function were assessed using electrophysiology in muscle specific Ulk1 knockout mice (MKO) and their littermate controls (LM). Specific peak-isometric torque of the ankle dorsiflexors (normalized by tibialis anterior muscle cross-sectional area) and specific force of the fast-twitch extensor digitorum longus muscles were reduced in MKO mice compared to LM mice (p<0.03). Permeabilized muscle fibers from MKO mice had greater mitochondrial content, yet lower mitochondrial oxygen consumption and greater reactive oxygen species production compared to fibers from LM mice (p[&le;] 0.04). Altered neuromuscular junction innervation patterns and changes in autophagosome numbers and/or flux in muscles from MKO may have contributed to decrements in contractile and metabolic function. Results from this study support an important role of Ulk1-mediated autophagy in skeletal muscle with age, reflecting Ulk1s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation. A lifetime of insufficient Ulk-1-mediated autophagy in skeletal muscle exacerbates age-related contractile and metabolic dysfunction.

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Nichenko, A. S., Sorensen, J. R., Southern, W. M., Qualls, A. E., Schifino, A. G., McFaline-Figueroa, J., Blum, J. E., Thalacker-Mercer, A. E., Greising, S. M., Call, J. A.. 2020-07-31. Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness. https://doi.org/10.1101/2020.07.31.223412

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