267P Circulating alpha-Klotho combats TGF-beta-induced sarcopenia

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.76
• Main Authors: Ohsawsa, Y., Nishimatsu, S., Saito, F., Sunada, Y.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.085

Deficiency of α-Klotho shortens lifespan with senescent phenotypes, including prominent muscle atrophy and weakness in mice. α-Klotho is mainly expressed in renal tubular epithelia as a single-pass plasma membrane protein; its C-terminal intracellular domain is cleaved by membrane-anchored proteases and secreted into systemic circulation. Thus, 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.