MOTS-c modulates skeletal muscle function by directly binding and activating CK2.

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2024-10-19 eCollection Date: 2024-11-15 DOI:10.1016/j.isci.2024.111212

Hiroshi Kumagai, Su-Jeong Kim, Brendan Miller, Hirofumi Zempo, Kumpei Tanisawa, Toshiharu Natsume, Shin Hyung Lee, Junxiang Wan, Naphada Leelaprachakul, Michi Emma Kumagai, Ricardo Ramirez, Hemal H Mehta, Kevin Cao, Tae Jung Oh, James A Wohlschlegel, Jihui Sha, Yuichiro Nishida, Noriyuki Fuku, Shohei Dobashi, Eri Miyamoto-Mikami, Mizuki Takaragawa, Mizuho Fuku, Toshinori Yoshihara, Hisashi Naito, Ryoko Kawakami, Suguru Torii, Taishi Midorikawa, Koichiro Oka, Megumi Hara, Chiharu Iwasaka, Yosuke Yamada, Yasuki Higaki, Keitaro Tanaka, Kelvin Yen, Pinchas Cohen

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引用次数: 0

Abstract

MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

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MOTS-c 通过直接结合和激活 CK2 来调节骨骼肌功能。

MOTS-c 是一种能改善新陈代谢的线粒体微蛋白。在这里，我们证明了 CK2 是 MOTS-c 的直接功能靶标。MOTS-c 可直接与 CK2 结合，并在无细胞系统中激活 CK2。给小鼠注射 MOTS-c 可防止骨骼肌萎缩并增强肌肉葡萄糖摄取，而抑制 CK2 的活性则会减弱这种作用。有趣的是，MOTS-c 的作用具有组织特异性。全身给药的 MOTS-c 可与脂肪和肌肉中的 CK2 结合，但在肌肉中会刺激 CK2 的活性，而在脂肪中则会通过对 CK2 相互作用蛋白的不同修饰而抑制 CK2 的活性。值得注意的是，一种天然存在的 MOTS-c 变异体 K14Q MOTS-c 与 CK2 的结合减少，不会激活 CK2 或引起其效应。男性 K14Q MOTS-c 基因携带者患肌肉疏松症和 2 型糖尿病（T2D）的风险较高，且与年龄和体力活动有关，而女性患 T2D 的风险则随着年龄的增长而降低。总之，这些发现提供了 CK2 是 MOTS-c 作用所必需的证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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