Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice
Takahiro Onoki,
Yoshihiro Izumi,
Masatomo Takahashi,
Shohei Murakami,
Daisuke Matsumaru,
Nao Ohta,
Sisca Meida Wati,
Nozomi Hatanaka,
Fumiki Katsuoka,
Mitsuharu Okutsu,
Yutaka Yabe,
Yoshihiro Hagiwara,
Makoto Kanzaki,
Takeshi Bamba,
Eiji Itoi,
Hozumi Motohashi
Affiliations
Takahiro Onoki
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan; Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, 980-8575, Japan
Yoshihiro Izumi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Masatomo Takahashi
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Shohei Murakami
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan
Daisuke Matsumaru
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan
Nao Ohta
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan
Sisca Meida Wati
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan
Nozomi Hatanaka
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
Fumiki Katsuoka
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan
Mitsuharu Okutsu
Graduate School of Science, Nagoya City University, Nagoya, 467-8501, Japan
Yutaka Yabe
Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, 980-8575, Japan
Yoshihiro Hagiwara
Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, 980-8575, Japan
Makoto Kanzaki
Graduate School of Biomedical Engineering, Tohoku University, Sendai, 980-8575, Japan
Takeshi Bamba
Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Eiji Itoi
Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, 980-8575, Japan
Hozumi Motohashi
Department of Gene Expression Regulation, IDAC, Tohoku University, Sendai, 980-8575, Japan; Corresponding author. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
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.
