A recent study published in Nature Aging has identified metabolic failure, specifically impaired branched-chain amino acid (BCAA) catabolism, as a key factor contributing to muscle loss in aging. The study, which integrates transcriptomic, metabolomic, and proteomic data, sheds light on the molecular and metabolic signatures associated with sarcopenia, a condition marked by progressive muscle deterioration in older adults.
Skeletal muscle, which accounts for about 40% of body mass, typically peaks in strength and mass during young adulthood but declines by 15-30% each decade after the age of 50. Sarcopenia not only weakens muscle function but also leads to frailty and higher mortality rates in older individuals. The underlying causes of sarcopenia have long been linked to inflammation, impaired protein synthesis, and mitochondrial dysfunction, but the new study provides a deeper look at metabolic dysregulation, particularly in BCAA metabolism.
BCAAs, which serve as a vital energy source during physical activity, are metabolized primarily in skeletal muscle. Previous animal studies have suggested that BCAA supplementation can boost muscle strength and mass, though results have been mixed. The new study, conducted at the West China Hospital of Sichuan University, reveals that in patients with sarcopenia, the catabolism of BCAAs is disrupted, leading to their accumulation in muscle tissue. This buildup, in turn, triggers abnormal activation of cellular pathways that cause muscle atrophy.
The study involved participants over the age of 65 who were recommended for knee surgery. Using multi-omics analysis, the researchers identified 453 differentially expressed genes among individuals diagnosed with sarcopenia, those at risk, and healthy controls. Key metabolic pathways, including oxidative phosphorylation, glycolysis, and BCAA catabolism, were found to be significantly altered in those with sarcopenia. Importantly, genes involved in BCAA catabolism, such as BCAT2 and BCKDHB, were downregulated, leading to an accumulation of BCAAs and dysregulated mTOR signaling, a known driver of muscle atrophy.
In animal models, impaired BCAA catabolism was shown to exacerbate muscle and fat tissue pathology, providing further evidence that restoring normal BCAA metabolism could slow the progression of sarcopenia.
These findings highlight the importance of metabolic dysfunction in muscle aging and suggest that interventions targeting BCAA catabolism could offer new avenues for treating or preventing sarcopenia in aging populations.
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