Circulating α-Klotho Counteracts Transforming Growth Factor-β-Induced Sarcopenia.

Autor:	Ohsawa Y; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan. Electronic address: yosawa@med.kawasaki-m.ac.jp., Ohtsubo H; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan., Munekane A; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan., Ohkubo K; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan., Murakami T; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan., Fujino M; Department of Health and Sports Science, Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Kurashiki, Japan., Nishimatsu SI; Department of Natural Sciences, Kawasaki Medical School, Kurashiki, Japan., Hagiwara H; Department of Medical Science, Teikyo University of Science, Tokyo, Japan., Nishimura H; Department of Pathology, Kawasaki Medical School, Kurashiki, Japan., Kaneko R; Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan., Suzuki T; Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan., Tatsumi R; Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture, Kyushu University, Fukuoka, Japan., Mizunoya W; Department of Food and Life Science, School of Life and Environmental Science, Azabu University, Sagamihara, Japan., Hinohara A; Research Coordination Group, Tokyo Research Park, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Fukunaga M; Kawasaki Medical School, Kurashiki, Japan., Sunada Y; Department of Neurology, Kawasaki Medical School, Kurashiki, Japan. Electronic address: ysunada@med.kawasaki-m.ac.jp.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2023 May; Vol. 193 (5), pp. 591-607. Date of Electronic Publication: 2023 Feb 10.
DOI:	10.1016/j.ajpath.2023.01.009
Abstrakt:	α-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. α-Klotho has two forms: membrane α-Klotho and circulating α-Klotho (c-α-Klotho). Loss of membrane α-Klotho impairs a phosphaturic effect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-α-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-α-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-β effector, became activated in skeletal muscle. Moreover, c-α-Klotho suppressed muscle-wasting TGF-β molecules, including myostatin, growth and differentiation factor 11, activin, and TGF-β1, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-α-Klotho reversed impaired in vitro myogenesis caused by these TGF-βs. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-βs, restored muscle atrophy and weakness in α-Klotho (-/-) mice and in elderly wild-type mice by suppression of activated Smad2 and up-regulated Cdkn1a (p21) transcript, a target of phosphorylated Smad2. Ki26894 also induced the slow to fast myofiber switch. These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-β-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-β blockade to prevent sarcopenia. (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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