Elsevier

Redox Biology

Volume 43, July 2021, 101966
Redox Biology

Research Paper
Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

https://doi.org/10.1016/j.redox.2021.101966Get rights and content
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Highlights

  • Systemic Keap1 knockdown enhances exercise endurance capacity in mice.

  • Keap1 deficiency in skeletal muscle activates NRF2 pathway.

  • Keap1 deficiency in skeletal muscle enhances endurance capacity in female mice.

  • Keap1 deficiency in skeletal muscle promotes exercise-induced fatty acid utilization.

Abstract

Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

Keywords

Exercise
Skeletal muscle
KEAP1-NRF2 system
Fatty acid
Beta-oxidation

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