Circulating a-Klotho Counteracts Transforming Growth Factor-b-Induced Sarcopenia

a-Klotho is a longevity-related protein. Its deficiency shortens lifespan with prominent senescent phenotypes, including muscle atrophy and weakness in mice. a-Klotho has two forms: membrane a-Klotho and circulating a-Klotho (c-a-Klotho). Loss of membrane a-Klotho impairs a phosphaturic ef-fect, thereby accelerating phosphate-induced aging. However, the mechanisms of senescence on c-a-Klotho loss remain largely unknown. Herein, with the aging of wild-type mice, c-a-Klotho declined, whereas Smad2, an intracellular transforming growth factor (TGF)-13 effector, became activated in skeletal muscle. Moreover, c-a-Klotho suppressed muscle-wasting TGF-13 molecules, including myo-statin, growth and differentiation factor 11, activin, and TGF-131, through binding to ligands as well as type I and type II serine/threonine kinase receptors. Indeed, c-a-Klotho reversed impaired in vitro myogenesis caused by these TGF-13s. Oral administration of Ki26894, a small-molecule inhibitor of type I receptors for these TGF-13s, restored muscle atrophy and weakness in a-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-a-Klotho's potential as a circulating inhibitor counteracting TGF-13-induced sarcopenia. These data highlight the potential of a novel therapy involving TGF-13 blockade to prevent sarcopenia. (Am J Pathol 2023, 193: 591-607; https://doi.org/10.1016/j.ajpath.2023.01.009)

Automated summary

a-Klotho is a protein related to longevity, and its deficiency leads to shortened lifespan and senescent phenotypes in mice, including muscle atrophy and weakness. The circulating form of a-Klotho (c-a-Klotho) suppresses muscle-wasting molecules induced by TGF-13 through ligand binding and receptor interaction. A small-molecule inhibitor of type I receptors for these TGF-13s, called Ki26894, can reverse muscle atrophy and weakness by suppressing activated Smad2 and up-regulating Cdkn1a transcript. These findings suggest the potential of c-a-Klotho as a circulating inhibitor to counteract TGF-13-induced sarcopenia, highlighting the possibility of a novel therapy involving TGF-13 blockade.