Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

Autor: Nichenko AS; Department of Kinesiology, University of Georgia, Athens, GA 30602, USA.; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Sorensen JR; School of Kinesiology, University of Minnesota, Minneapolis, MN 55455, USA., Southern WM; Department of Kinesiology, University of Georgia, Athens, GA 30602, USA.; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Qualls AE; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Schifino AG; Department of Kinesiology, University of Georgia, Athens, GA 30602, USA.; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., McFaline-Figueroa J; Department of Kinesiology, University of Georgia, Athens, GA 30602, USA.; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Blum JE; Division of Nutrition Science, Cornell University, Ithaca, NY 14850, USA., Tehrani KF; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Yin H; Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA., Mortensen LJ; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA., Thalacker-Mercer AE; Division of Nutrition Science, Cornell University, Ithaca, NY 14850, USA.; Department of Cell, Developmental and Integrative Biology, University of Alabama, Birmingham, AL 35294, USA., Greising SM; School of Kinesiology, University of Minnesota, Minneapolis, MN 55455, USA., Call JA; Department of Kinesiology, University of Georgia, Athens, GA 30602, USA.; Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2021 Feb 16; Vol. 22 (4). Date of Electronic Publication: 2021 Feb 16.
DOI: 10.3390/ijms22041937
Abstrakt: The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of skeletal muscle aging. 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. 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 was 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 ≤ 0.04). Alterations in neuromuscular junction innervation patterns as well as changes to autophagosome assembly and flux were explored as possible contributors to the pathological features in Ulk1 deficiency. Of primary interest, we found that Ulk1 phosphorylation (activation) to total Ulk1 protein content was reduced in older muscles compared to young muscles from both human and mouse, which may contribute to decreased autophagy flux and an accumulation of dysfunctional mitochondria. Results from this study support the role of Ulk1-mediated autophagy in aging skeletal muscle, reflecting Ulk1's dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.
Databáze: MEDLINE
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