Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle. Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.