Loss of Myostatin Alters Mitochondrial Oxidative Phosphorylation, TCA Cycle Activity, and ATP Production in Skeletal Muscle
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Published:2022-12-11
Issue:24
Volume:23
Page:15707
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Wang Xueqiao, Wei ZhuyingORCID, Gu MingjuanORCID, Zhu Lin, Hai Chao, Di Anqi, Wu DiORCID, Bai Chunling, Su Guanghua, Liu Xuefei, Yang Lei, Li Guangpeng
Abstract
Myostatin (MSTN) is an important negative regulator of skeletal muscle growth in animals. A lack of MSTN promotes lipolysis and glucose metabolism but inhibits oxidative phosphorylation (OXPHOS). Here, we aimed to investigate the possible mechanism of MSTN regulating the mitochondrial energy homeostasis of skeletal muscle. To this end, MSTN knockout mice were generated by the CRISPR/Cas9 technique. Expectedly, the MSTN null (Mstn−/−) mouse has a hypermuscular phenotype. The muscle metabolism of the Mstn−/− mice was detected by an enzyme-linked immunosorbent assay, indirect calorimetry, ChIP-qPCR, and RT-qPCR. The resting metabolic rate and body temperature of the Mstn−/− mice were significantly reduced. The loss of MSTN not only significantly inhibited the production of ATP by OXPHOS and decreased the activity of respiratory chain complexes, but also inhibited key rate-limiting enzymes related to the TCA cycle and significantly reduced the ratio of NADH/NAD+ in the Mstn−/− mice, which then greatly reduced the total amount of ATP. Further ChIP-qPCR results confirmed that the lack of MSTN inhibited both the TCA cycle and OXPHOS, resulting in decreased ATP production. The reason may be that Smad2/3 is not sufficiently bound to the promoter region of the rate-limiting enzymes Idh2 and Idh3a of the TCA cycle, thus affecting their transcription.
Funder
Inner Mongolia Autonomous Region Open Competition Projects Inner Mongolia Autonomous Region Science and Technology Major Project Inner Mongolia Autonomous Region Science and Technology Leading Talent Team Inner Mongolia Hohhot City Science and Technology Project Engineering Research Center of the Ministry of Education on Excellent Livestock Scale Breeding Technology Inner Mongolia University Chief Scientist Program
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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