Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging
Naoki Ito,
Ai Takatsu,
Hiromi Ito,
Yuka Koike,
Kiyoshi Yoshioka,
Yasutomi Kamei,
Shin-ichiro Imai
Affiliations
Naoki Ito
AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan
Ai Takatsu
AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan
Hiromi Ito
AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan
Yuka Koike
AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan
Kiyoshi Yoshioka
Institute for Research on Productive Aging (IRPA), Tokyo, Japan; Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
Yasutomi Kamei
Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
Shin-ichiro Imai
AMED Frailty Research Laboratory (Teijin), AMED Cyclic Innovation for Clinical Empowerment (CiCLE), Osaka, Japan; Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan; Department of Developmental Biology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Corresponding author
Summary: Sarcopenia and frailty are urgent socio-economic problems worldwide. Here we demonstrate a functional connection between the lateral hypothalamus (LH) and skeletal muscle through Slc12a8, a recently identified nicotinamide mononucleotide transporter, and its relationship to sarcopenia and frailty. Slc12a8-expressing cells are mainly localized in the LH. LH-specific knockdown of Slc12a8 in young mice decreases activity-dependent energy and carbohydrate expenditure and skeletal muscle functions, including muscle mass, muscle force, intramuscular glycolysis, and protein synthesis. LH-specific Slc12a8 knockdown also decreases sympathetic nerve signals at neuromuscular junctions and β2-adrenergic receptors in skeletal muscle, indicating the importance of the LH-sympathetic nerve-β2-adrenergic receptor axis. LH-specific overexpression of Slc12a8 in aged mice significantly ameliorates age-associated decreases in energy expenditure and skeletal muscle functions. Our results highlight an important role of Slc12a8 in the LH for regulation of whole-body metabolism and skeletal muscle functions and provide insights into the pathogenesis of sarcopenia and frailty during aging.
