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

Abstract

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.

• Authors: Yutaka Ohsawa, Hideaki Ohtsubo, Asami Munekane, Kohei Ohkubo, Tatsufumi Murakami, Masahiro Fujino, Shin-Ichiro Nishimatsu, Hiroki Hagiwara, Hirotake Nishimura, Ryuki Kaneko, Takahiro Suzuki, Ryuichi Tatsumi, Wataru Mizunoya, Atsushi Hinohara, Masao Fukunaga, Yoshihide Sunada
• Journal: The American journal of pathology (Am J Pathol) Vol. 193 Issue 5 Pg. 591-607 (05 2023) ISSN: 1525-2191 [Electronic] United States
• PMID: 36773783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Transforming Growth Factor beta
• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Transforming Growth Factor beta1
• Transforming Growth Factors

Topics

• Mice
• Animals
• Transforming Growth Factor beta
• Receptors, Transforming Growth Factor beta (metabolism)
• Sarcopenia (prevention & control)
• Protein Serine-Threonine Kinases (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Transforming Growth Factors