Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783658190256209920 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7919824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT nichenkoannas lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT sorensenjacobr lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT southernwmichael lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT quallsanitae lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT schifinoalbinog lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT mcfalinefigueroajennifer lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT blumjamiee lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT tehranikayvanf lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT yinhang lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT mortensenlukej lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT thalackermercerannae lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT greisingsarahm lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness AT calljarroda lifelongulk1mediatedautophagydeficiencyinmuscleinducesmitochondrialdysfunctionandcontractileweakness |