Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

Anna S. Nichenko; Jacob R. Sorensen; W. Michael Southern; Anita E. Qualls; Albino G. Schifino; Jennifer McFaline-Figueroa; Jamie E. Blum; Kayvan F. Tehrani; Hang Yin; Luke J. Mortensen; Anna E. Thalacker-Mercer; Sarah M. Greising; Jarrod A. Call

doi:10.3390/ijms22041937

Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

Anna S. Nichenko, Jacob R. Sorensen, W. Michael Southern, Anita E. Qualls, Albino G. Schifino, Jennifer McFaline-Figueroa, Jamie E. Blum, Kayvan F. Tehrani, Hang Yin, Luke J. Mortensen, Anna E. Thalacker-Mercer, Sarah M. Greising, Jarrod A. Call

Kinesiology

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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 as-sessed 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, reflect-ing Ulk1′s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

Original language	English (US)
Article number	1937
Pages (from-to)	1-20
Number of pages	20
Journal	International journal of molecular sciences
Volume	22
Issue number	4
DOIs	https://doi.org/10.3390/ijms22041937
State	Published - Feb 2 2021

Bibliographical note

Funding Information:
Funding: We acknowledge Georgia Partners in Medicine REM seed grant (to J.A.C.), and the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to JAC and SMG). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1650441 (to J.E.B.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Aging
Autophagy flux
Mitophagy
Neuromuscular junction
Sarcopenia

Access

10.3390/ijms22041937

OpenUrl availability

Full text

Cite this

Nichenko, A. S., Sorensen, J. R., Southern, W. M., Qualls, A. E., Schifino, A. G., McFaline-Figueroa, J., Blum, J. E., Tehrani, K. F., Yin, H., Mortensen, L. J., Thalacker-Mercer, A. E., Greising, S. M., & Call, J. A. (2021). Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness. International journal of molecular sciences, 22(4), 1-20. Article 1937. https://doi.org/10.3390/ijms22041937

Nichenko, AS, Sorensen, JR, Southern, WM, Qualls, AE, Schifino, AG, McFaline-Figueroa, J, Blum, JE, Tehrani, KF, Yin, H, Mortensen, LJ, Thalacker-Mercer, AE, Greising, SM & Call, JA 2021, 'Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness', International journal of molecular sciences, vol. 22, no. 4, 1937, pp. 1-20. https://doi.org/10.3390/ijms22041937

@article{bc454b79f9f04cf5b39f85e3d90577cb,

title = "Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness",

abstract = "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 as-sessed 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, reflect-ing Ulk1′s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.",

keywords = "Aging, Autophagy flux, Mitophagy, Neuromuscular junction, Sarcopenia",

author = "Nichenko, {Anna S.} and Sorensen, {Jacob R.} and Southern, {W. Michael} and Qualls, {Anita E.} and Schifino, {Albino G.} and Jennifer McFaline-Figueroa and Blum, {Jamie E.} and Tehrani, {Kayvan F.} and Hang Yin and Mortensen, {Luke J.} and Thalacker-Mercer, {Anna E.} and Greising, {Sarah M.} and Call, {Jarrod A.}",

note = "Funding Information: Funding: We acknowledge Georgia Partners in Medicine REM seed grant (to J.A.C.), and the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to JAC and SMG). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1650441 (to J.E.B.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = feb,

day = "2",

doi = "10.3390/ijms22041937",

language = "English (US)",

volume = "22",

pages = "1--20",

journal = "International journal of molecular sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "4",

}

TY - JOUR

T1 - Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

AU - Nichenko, Anna S.

AU - Sorensen, Jacob R.

AU - Southern, W. Michael

AU - Qualls, Anita E.

AU - Schifino, Albino G.

AU - McFaline-Figueroa, Jennifer

AU - Blum, Jamie E.

AU - Tehrani, Kayvan F.

AU - Yin, Hang

AU - Mortensen, Luke J.

AU - Thalacker-Mercer, Anna E.

AU - Greising, Sarah M.

AU - Call, Jarrod A.

N1 - Funding Information: Funding: We acknowledge Georgia Partners in Medicine REM seed grant (to J.A.C.), and the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Clinical & Rehabilitative Medicine Research Program, FY17 Neuromusculoskeletal Injuries Rehabilitation Research Award (W81XWH-18-1-0710 to JAC and SMG). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1650441 (to J.E.B.). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/2/2

Y1 - 2021/2/2

N2 - 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 as-sessed 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, reflect-ing Ulk1′s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

AB - 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 as-sessed 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, reflect-ing Ulk1′s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

KW - Aging

KW - Autophagy flux

KW - Mitophagy

KW - Neuromuscular junction

KW - Sarcopenia

UR - http://www.scopus.com/inward/record.url?scp=85101028304&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85101028304&partnerID=8YFLogxK

U2 - 10.3390/ijms22041937

DO - 10.3390/ijms22041937

M3 - Article

C2 - 33669246

AN - SCOPUS:85101028304

SN - 1661-6596

VL - 22

SP - 1

EP - 20

JO - International journal of molecular sciences

JF - International journal of molecular sciences

IS - 4

M1 - 1937

ER -

Lifelong ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

Abstract

Bibliographical note

Keywords

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this