Impaired Lactate Metabolism in Liver and Muscle as an Important Cause of Sarcopenia
Sarcopenia is the name given to severe age-related loss of muscle mass and strength. This loss occurs steadily throughout later life. The present state of research into this condition is representative of aging more generally, in that while a range of quite different mechanisms all have strong supporting evidence for a meaningful contribution to sarcopenia, their relative importance to one another is unclear, how they connect to one another at the detail level is unclear, which are largely causes and which are largely consequences of one another, and their relationship to the known underlying forms of cell and tissue damage that drive aging is unclear. See the evidence for loss of muscle stem cell function to be the primary cause of sarcopenia, and surrounding discussions on that topic, for example. Here, researchers point instead to disruption of lactate metabolism in both liver and muscle tissue as the primary cause of sarcopenia; the involvement of the liver a reminder that no one tissue stands alone in the matter of aging. All organs communicate with one another and are interdependent in many different ways.
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.