Cell Rep. Med. 3, 100633 (2022)
Mitochondrial dysfunction is a hallmark of aging and is associated with age-related deterioration of skeletal muscle. Thus, improving mitochondrial health is potentially a promising strategy to improve muscle health. Exercise has been shown to promote mitophagy, which is a selective form of autophagy that can help to remove or recycle superfluous and/or dysfunctional mitochondria. In preclinical models, stimulating mitophagy has been a beneficial therapeutic approach to rescue the age-associated muscle deterioration, but there is very limited evidence in humans. Urolithin A (UA), a gut-microbiome-derived postbiotic metabolite that is present in foods such as berries and walnuts, has been shown to induce mitophagy and improve muscle function in preclinical animal models. In Cell Reports Medicine, Singh and colleagues report a new proof-of-concept randomized trial on the efficacy of long-term (4 month) oral supplementation of UA (500 mg or 1,000 mg) or placebo (control) on muscle function in middle-aged (40 to 64 years old) adults who are overweight and have low physical endurance. Assessment of clinical and physiological outcomes linked to muscle strength, exercise tolerance and physical performance were conducted. Plasma samples were collected to assess the effect of UA on metabolites and cytokines associated with cellular health. Skeletal-muscle biopsies were collected to analyze the effect of UA on the muscle transcriptome and proteome, to validate the impact of this postbiotic metabolite on proteins linked to mitochondrial health. The authors report that UA was safe and well-tolerated during the four-month period, even at the higher dose. Individuals supplemented with UA exhibited improvements in muscle strength and exercise-performance measures (such as aerobic endurance and physical performance) in a dose-dependent manner. These phenotypic changes correlated with an increase in circulating levels of UA, in parallel with reduced plasma acylcarnitines and C-reactive protein upon UA supplementation, which indicates higher mitochondrial efficiency and reduced inflammation. Furthermore, evidence from skeletal-muscle biopsies further reinforced signatures of improved mitochondrial metabolism and mitophagy following UA supplementation. Singh et al. provide clinical and molecular evidence for UA-supplementation-induced improvement in physical performance in the absence of exercise in middle-aged individuals, with potential for a wide beneficial impact on muscle health in the general aging population.
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