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Nutrients are essential for improving mitochondrial function and skeletal muscle health during the aging process. Betaine is a nutrient with potential muscle\u2010preserving properties. However, whether and how betaine could regulate the mitochondria function in aging muscle are poorly understood. We aimed to explore the molecular target and underlying mechanism of betaine in attenuating the age\u2010related mitochondrial dysfunction in skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Young mice (YOU, 2\u00a0months), old mice (OLD, 15\u00a0months), and old mice with betaine treatment (BET, 15\u00a0months) were fed for 12\u00a0weeks. The effects of betaine on muscle mass, strength, function, and subcellular structure of muscle fibres were assessed. RNA sequencing (RNA\u2010seq) was conducted to identify the molecular target of betaine. The impacts of betaine on mitochondrial\u2010related molecules, superoxide accumulation, and oxidative respiration were examined using western blotting (WB), immunofluorescence (IF) and seahorse assay. The underlying mechanism of betaine regulation on the molecular target to maintain mitochondrial function was investigated by luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay. Adenoassociated virus transfection, succinate dehydrogenase staining (SDH), and energy expenditure assessment were performed on 20\u2010month\u2010old mice for validating the mechanism <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Betaine intervention demonstrated anti\u2010aging effects on the muscle mass (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.017), strength (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.010), and running distance (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.013). Mitochondrial\u2010related markers (ATP5a, Sdha, and Uqcrc2) were 1.1\u2010 to 1.5\u2010fold higher in BET than OLD (all <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.036) with less wasted mitochondrial vacuoles accumulating in sarcomere. Bioinformatic analysis from RNA\u2010seq displayed pathways related to mitochondrial respiration activity was higher enriched in BET group (NES\u00a0=\u00a0\u22120.87, FDR\u00a0=\u00a00.10). The quantitative real time PCR (qRT\u2010PCR) revealed betaine significantly reduced the expression of a novel mitochondrial regulator, Mss51 (\u221224.9%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.002). In C2C12 cells, betaine restored the Mss51\u2010mediated suppression in mitochondrial respiration proteins (all <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.041), attenuated oxygen consumption impairment, and superoxide accumulation (by 20.7%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001). Mechanically, betaine attenuated aging\u2010induced repression in <jats:italic>Yy1<\/jats:italic> mRNA expression (BET vs. OLD: 2.06 vs. 1.02, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.009). Yy1 transcriptionally suppressed <jats:italic>Mss51<\/jats:italic> mRNA expression both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. This contributed to the preservation of mitochondrial respiration, improvement for energy expenditure (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.008), and delay of muscle loss during aging process.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Altogether, betaine transcriptionally represses <jats:italic>Mss51<\/jats:italic> via Yy1, improving age\u2010related mitochondrial respiration in skeletal muscle. These findings suggest betaine holds promise as a dietary supplement to delay skeletal muscle degeneration and improve age\u2010related mitochondrial diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13558","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T04:34:32Z","timestamp":1724733272000},"page":"2104-2117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Betaine delays age\u2010related muscle loss by mitigating Mss51\u2010induced impairment in mitochondrial respiration via Yin Yang1"],"prefix":"10.1002","volume":"15","author":[{"given":"Si","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Nutrition, School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health Sun Yat\u2010sen University  Guangzhou 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Yat\u2010sen University Cancer Center Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nutrition, School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"School of Public Health, Guangdong Provincial Key Laboratory of Food, Nutrition and Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenge","family":"Huang","sequence":"additional","affiliation":[{"name":"Center of Experimental Animals Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nutrition, School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"School of Public Health, Guangdong Provincial Key Laboratory of Food, 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