A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.

Xirouchaki, CE; García-Domínguez, E; Coughlan, E; McGrath, MJ; Giri, S; Liang, S; Wiede, F; Bigot, A; Sadoshima, J; Gomez-Cabrera, MC; Philp, A; Moberg, M; Apró, W; Roman, W; Mitchell, CA; Tiganis, T

A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.

Xirouchaki, CE García-Domínguez, E Coughlan, E McGrath, MJ Giri, S Liang, S Wiede, F Bigot, A Sadoshima, J Gomez-Cabrera, MC Philp, A

Moberg, M Apró, W Roman, W Mitchell, CA Tiganis, T

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Publisher:: AMER ASSOC ADVANCEMENT SCIENCE
Publication Type:: Journal Article
Citation:: Sci Adv, 2026, 12, (24), pp. eadz1953
Issue Date:: 2026-06-12

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Field	Value	Language
dc.contributor.author	Xirouchaki, CE
dc.contributor.author	García-Domínguez, E
dc.contributor.author	Coughlan, E
dc.contributor.author	McGrath, MJ
dc.contributor.author	Giri, S
dc.contributor.author	Liang, S
dc.contributor.author	Wiede, F
dc.contributor.author	Bigot, A
dc.contributor.author	Sadoshima, J
dc.contributor.author	Gomez-Cabrera, MC
dc.contributor.author	Philp, A https://orcid.org/0000-0003-3860-4136
dc.contributor.author	Moberg, M
dc.contributor.author	Apró, W
dc.contributor.author	Roman, W
dc.contributor.author	Mitchell, CA
dc.contributor.author	Tiganis, T
dc.date.accessioned	2026-10-28T05:52:01Z
dc.date.available	2026-10-28T05:52:01Z
dc.date.issued	2026-06-12
dc.identifier.citation	Sci Adv, 2026, 12, (24), pp. eadz1953
dc.identifier.issn	2375-2548
dc.identifier.issn	2375-2548
dc.identifier.uri	http://hdl.handle.net/10453/197279
dc.description.abstract	A decline in nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartof	Sci Adv
dc.relation.isbasedon	10.1126/sciadv.adz1953
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	NADPH Oxidase 4
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Aging
dc.subject.mesh	Homeostasis
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	NF-E2-Related Factor 2
dc.subject.mesh	Physical Conditioning, Animal
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Oxidative Stress
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Male
dc.subject.mesh	Sarcopenia
dc.subject.mesh	Adaptation, Physiological
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Physical Conditioning, Animal
dc.subject.mesh	Adaptation, Physiological
dc.subject.mesh	Oxidative Stress
dc.subject.mesh	Aging
dc.subject.mesh	Homeostasis
dc.subject.mesh	Male
dc.subject.mesh	NF-E2-Related Factor 2
dc.subject.mesh	Sarcopenia
dc.subject.mesh	NADPH Oxidase 4
dc.subject.mesh	Animals
dc.subject.mesh	NADPH Oxidase 4
dc.subject.mesh	Muscle, Skeletal
dc.subject.mesh	Aging
dc.subject.mesh	Homeostasis
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	NF-E2-Related Factor 2
dc.subject.mesh	Physical Conditioning, Animal
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Oxidative Stress
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Male
dc.subject.mesh	Sarcopenia
dc.subject.mesh	Adaptation, Physiological
dc.title	A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
dc.type	Journal Article
utslib.citation.volume	12
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Health/School of Human Performance, Rehab & Population Health
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Human Performance Research Centre (HPRC)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2026-10-28T05:51:44Z
pubs.issue	24
pubs.publication-status	Published
pubs.volume	12
utslib.citation.issue	24

Abstract:

A decline in nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/197279