@article{15e8bb8600444b21bc41fd51f2bb6365,
title = "Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice",
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 = "Beta-oxidation, Exercise, Fatty acid, KEAP1-NRF2 system, Skeletal muscle",
author = "Takahiro Onoki and Yoshihiro Izumi and Masatomo Takahashi and Shohei Murakami and Daisuke Matsumaru and Nao Ohta and Wati, {Sisca Meida} and Nozomi Hatanaka and Fumiki Katsuoka and Mitsuharu Okutsu and Yutaka Yabe and Yoshihiro Hagiwara and Makoto Kanzaki and Takeshi Bamba and Eiji Itoi and Hozumi Motohashi",
note = "Funding Information: Keap1-knockdown (Keap1-KD) mice [ 19 ] were provided by Professor Masi Yamamoto at Tohoku University. Keap1 F/F mice were provided by Professor Shyam Biswal at Johns Hopkins University [ 20 ]. Mlc1f-Cre mice were provided by Professor Steve Burden at New York University [ 21 ]. All the mice utilized in this study were in the C57BL/6J genetic background. These mice were bred and housed under specific pathogen-free conditions with standard animal maintenance according to the regulations of The Standards for Human Care and Use of Laboratory Animals of Tohoku University (Tohoku University. 2007. Standards for human care and use of laboratory animals of Tohoku University. Tohoku University, Sendai, Japan.) and The Guidelines for Proper Conduct of Animal Experiments by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Science Council of Japan. 2006. Guidelines for proper conduct of animal experiments. Science Council of Japan, Ministry of Education, Culture, Sports, Science, and Technology of Japan, Tokyo, Japan.). Mice were examined at 2–5 months of age. After mice were sacrificed by cervical dislocation, the soleus (Sol), plantaris (Plant), gastrocnemius (GC) muscles, heart, lung and liver were subsequently dissected for analysis. The tibia length was measured using caliper. Blood was drawn from anesthetized mice using heparinized capillary tubes (Fisher Scientific) into the microtube within 0.5 M EDTA (pH 7.4, 2 μL) and centrifuged (3000 rpm for 15 min at 4 °C) to isolate plasma. Samples were frozen in liquid nitrogen and stored at −80 °C until analysis. Funding Information: We thank Professor Masi Yamamoto, Professor Shyam Biswal and Professor Steve Burden for providing Keap1 knockdown mice, Keap1 floxed mice and Mlc1f-Cre mice, respectively. We also thank the Biomedical Research Cores of the Tohoku University Graduate School of Medicine and Institute of Development, Aging and Cancer for providing technical support. This work was supported by JSPS [grant numbers 18H02621 (HM), 20H04832 (HM) 17H06299 (TB), and 17H06304 (TB)], the Naito Foundation (HM), a research grant from the Princess Takamatsu Cancer Research Fund [grant number 15–24728 (HM)], the Uehara Memorial Foundation (HM), AMED [grant number JP20gm5010002 (HM)] and Japan-Sweden Research Cooperative Program between JSPS and STINT [grant number JPJSBP120195402 (HM)]. The funders had no role in the study design, data collection and analysis, decision to publish or manuscript preparation. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = jul,
doi = "10.1016/j.redox.2021.101966",
language = "English",
volume = "43",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier BV",
}