PMID- 36564038 OWN - NLM STAT- MEDLINE DCOM- 20230203 LR - 20230403 IS - 2190-6009 (Electronic) IS - 2190-5991 (Print) IS - 2190-5991 (Linking) VI - 14 IP - 1 DP - 2023 Feb TI - Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1-Arih2 axis. PG - 606-621 LID - 10.1002/jcsm.13166 [doi] AB - BACKGROUND: Sarcopenia, the age-related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown. METHODS: The human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. d-Galactose (d-gal)-induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real-time polymerase chain reaction, RNA interference or overexpression, dual-luciferase reporter assay, RNA sequencing and untargeted metabolomics. RESULTS: We identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (-50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97-fold, P < 0.001 and +3.79-fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (-46%, P < 0.01 and -27%, P < 0.05; +1.8-fold, P < 0.01), myogenic differentiation (MyoD) (-55%, P < 0.001 and -34%, P < 0.01; +2.27-fold, P < 0.001), myogenin (MyoG) (-60%, P < 0.001 and -70%, P < 0.001; +5.46-fold, P < 0.001) and myosin heavy chain (MyHC) (-70%, P < 0.001 and -69%, P < 0.001; +3.44-fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up-regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23-fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18-fold, P < 0.001)-mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved d-gal-induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross-sectional area (1.19-fold to 1.5-fold, P < 0.01, P < 0.05 and P < 0.001). CONCLUSIONS: The comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1-Arih2 axis and may serve as a therapeutic target in sarcopenia. CI - (c) 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders. FAU - Jiang, Xuan AU - Jiang X AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Ji, Siyu AU - Ji S AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Yuan, Fenglai AU - Yuan F AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. AD - Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China. FAU - Li, Tushuai AU - Li T AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Cui, Siyuan AU - Cui S AD - Wuxi No. 2 People's Hospital, Wuxi, China. FAU - Wang, Wei AU - Wang W AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Ye, Xianlong AU - Ye X AD - Ganjiang Chinese Medicine Innovation Center, Nanchang, China. FAU - Wang, Rong AU - Wang R AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Chen, Yongquan AU - Chen Y AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Translational Medicine, Jiangnan University, Wuxi, China. FAU - Zhu, Shenglong AU - Zhu S AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. AD - School of Translational Medicine, Jiangnan University, Wuxi, China. LA - eng GR - 82000808/National Natural Science Foundation of China/ GR - BK20221091/Natural Science Foundation of Jiangsu Province/ GR - 2022M711369/Chinese Postdoctoral Science Foundation/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221223 PL - Germany TA - J Cachexia Sarcopenia Muscle JT - Journal of cachexia, sarcopenia and muscle JID - 101552883 RN - EC 1.- (Oxidoreductases) RN - 0 (Pyruvates) RN - 0 (FOXP1 protein, human) RN - 0 (Repressor Proteins) RN - 0 (Forkhead Transcription Factors) RN - EC 2.3.2.27 (ARIH2 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - 0 (Foxp1 protein, mouse) SB - IM MH - Aged MH - Humans MH - Mice MH - Animals MH - *Sarcopenia/metabolism MH - Myoblasts/metabolism MH - Cell Differentiation/genetics MH - Oxidoreductases/metabolism/pharmacology MH - Pyruvates/metabolism/pharmacology MH - Repressor Proteins MH - Forkhead Transcription Factors MH - Ubiquitin-Protein Ligases/metabolism PMC - PMC9891931 OTO - NOTNLM OT - PDHB OT - ageing OT - myogenesis OT - sarcopenia COIS- The authors declare no competing interests related to this study. All the mouse experiments were performed in accordance with the local and national ethical regulations. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle. EDAT- 2022/12/24 06:00 MHDA- 2023/02/04 06:00 PMCR- 2022/12/23 CRDT- 2022/12/23 19:52 PHST- 2022/11/15 00:00 [revised] PHST- 2022/07/12 00:00 [received] PHST- 2022/11/25 00:00 [accepted] PHST- 2022/12/24 06:00 [pubmed] PHST- 2023/02/04 06:00 [medline] PHST- 2022/12/23 19:52 [entrez] PHST- 2022/12/23 00:00 [pmc-release] AID - JCSM13166 [pii] AID - 10.1002/jcsm.13166 [doi] PST - ppublish SO - J Cachexia Sarcopenia Muscle. 2023 Feb;14(1):606-621. doi: 10.1002/jcsm.13166. Epub 2022 Dec 23.