MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

Wu Yang,Yong-Xin Wu,Zhi-Yin Liao,Ai Guo,Yun-Fei Yang,Jiang-Hao Wu,Jing Yu,Jing Zhou,Zhen Fan,Qian Xiao,Qiu-Nan Chen

doi:10.1038/s41419-021-04400-5

Abstract

Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by d-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

Highlights

Skeletal muscle plays an essential role in metabolic health and physical function [1]
In caspase-9 was increased [31] [Fig. 2J]. These results indicate that addition, MICU3 has been discovered as a new mitochondrial calcium uniporter (MCU) regulator in knockdown of MICU3 could induce mitochondrial disorder and the nervous system, which could increase mitochondrial Ca2+ apoptosis
MICU3 was downregulated in skeletal muscle from aged mice energy X-ray absorptiometry (DEXA) results exhibited that the lean and senescent C2C12 cells induced by D-gal mass of the old control (OC, 26M) group was lower than the adult

Summary

INTRODUCTION

Skeletal muscle plays an essential role in metabolic health and physical function [1]. In caspase-9 was increased [31] [Fig. 2J] These results indicate that addition, MICU3 has been discovered as a new MCU regulator in knockdown of MICU3 could induce mitochondrial disorder and the nervous system, which could increase mitochondrial Ca2+ apoptosis. According to the RT-PCR and western blot data, injection of to the oxidative stress production and apoptotic process during MICU3-overexpression AAV9 resulted in an increase in gastroaging. Overexpression of MICU3 effectively alleviated the cnemius muscle MICU3 expression compared to controls [Fig. 3B, loss of skeletal muscle mass and function via promoting mitochondrial Ca2+ homeostasis to inhibit ROS-mediated apoptosis. These findings suggest that upregulating MICU3 expression. The exhausted exercise results demonstrated that, compared to the AC group, aging decreased the skeletal muscle function in the OC group, but overexpression of MICU3 in aged

RESULTS

DISCUSSION

MATERIALS AND METHODS

Findings

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