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

Chrysovalantou E Xirouchaki1,2, Esther García-Domínguez3,4, Eamon Coughlan1,2

  • 1Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Science Advances
|June 10, 2026
PubMed

Insights

Aging reduces skeletal muscle NADPH oxidase 4 (NOX4), impairing adaptive homeostasis and leading to sarcopenia. Restoring NOX4 or activating NFE2L2 can reverse age-related decline and frailty.

Area of Science:

  • Gerontology
  • Molecular Biology
  • Muscle Physiology

Background:

  • Aging is associated with declining adaptive homeostasis and increased oxidative stress.
  • Nuclear factor erythroid 2-related factor 2 (NFE2L2) signaling is crucial for cellular defense against oxidative damage.
  • NADPH oxidase 4 (NOX4) in skeletal muscle induces NFE2L2 adaptive responses.

Purpose of the Study:

  • To investigate the role of skeletal muscle NOX4 in aging-related adaptive homeostasis decline.
  • To determine the consequences of NOX4 deficiency in skeletal muscle during aging.
  • To explore therapeutic strategies for mitigating age-associated muscle dysfunction.

Main Methods:

  • Assessed NOX4 and NFE2L2 levels in aged mice and humans.
  • Generated skeletal muscle-specific NOX4 knockout mice.
  • Utilized viral gene delivery and pharmacological activation (sulforaphane) to restore NOX4 or NFE2L2 function.
  • Evaluated physiological parameters including muscle function, body composition, inflammation, insulin resistance, and liver health.

Main Results:

  • Skeletal muscle NOX4 levels decrease with age in mice and humans, correlating with reduced NFE2L2 activity.
  • Skeletal muscle-specific NOX4 deletion in aged mice accelerated aging phenotypes, causing sarcopenia, frailty, inflammation, insulin resistance, and liver disease.
  • Restoration of NOX4 or NFE2L2 activation ameliorated these age-related declines, reinstating exercise-like adaptive responses.

Conclusions:

  • Declining skeletal muscle NOX4 is a key driver of impaired NFE2L2-mediated adaptive homeostasis during aging.
  • NOX4 deficiency exacerbates age-related sarcopenia and systemic metabolic dysfunction.
  • Targeting NOX4 or NFE2L2 pathways offers potential therapeutic avenues for promoting healthy aging and combating age-related diseases.

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