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

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...

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Autores principales: Nichenko, Anna S., Sorensen, Jacob R., Southern, W. Michael, Qualls, Anita E., Schifino, Albino G., McFaline-Figueroa, Jennifer, Blum, Jamie E., Tehrani, Kayvan F., Yin, Hang, Mortensen, Luke J., Thalacker-Mercer, Anna E., Greising, Sarah M., Call, Jarrod A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919824/
https://www.ncbi.nlm.nih.gov/pubmed/33669246
http://dx.doi.org/10.3390/ijms22041937
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author Nichenko, Anna S.
Sorensen, Jacob R.
Southern, W. Michael
Qualls, Anita E.
Schifino, Albino G.
McFaline-Figueroa, Jennifer
Blum, Jamie E.
Tehrani, Kayvan F.
Yin, Hang
Mortensen, Luke J.
Thalacker-Mercer, Anna E.
Greising, Sarah M.
Call, Jarrod A.
author_facet Nichenko, Anna S.
Sorensen, Jacob R.
Southern, W. Michael
Qualls, Anita E.
Schifino, Albino G.
McFaline-Figueroa, Jennifer
Blum, Jamie E.
Tehrani, Kayvan F.
Yin, Hang
Mortensen, Luke J.
Thalacker-Mercer, Anna E.
Greising, Sarah M.
Call, Jarrod A.
author_sort Nichenko, Anna S.
collection PubMed
description 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.
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spelling pubmed-79198242021-03-02 Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness Nichenko, Anna S. Sorensen, Jacob R. Southern, W. Michael Qualls, Anita E. Schifino, Albino G. McFaline-Figueroa, Jennifer Blum, Jamie E. Tehrani, Kayvan F. Yin, Hang Mortensen, Luke J. Thalacker-Mercer, Anna E. Greising, Sarah M. Call, Jarrod A. Int J Mol Sci Article 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. MDPI 2021-02-16 /pmc/articles/PMC7919824/ /pubmed/33669246 http://dx.doi.org/10.3390/ijms22041937 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nichenko, Anna S.
Sorensen, Jacob R.
Southern, W. Michael
Qualls, Anita E.
Schifino, Albino G.
McFaline-Figueroa, Jennifer
Blum, Jamie E.
Tehrani, Kayvan F.
Yin, Hang
Mortensen, Luke J.
Thalacker-Mercer, Anna E.
Greising, Sarah M.
Call, Jarrod A.
Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title_full Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title_fullStr Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title_full_unstemmed Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title_short Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness
title_sort lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919824/
https://www.ncbi.nlm.nih.gov/pubmed/33669246
http://dx.doi.org/10.3390/ijms22041937
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