Single-cell ATAC sequencing of murine liver nuclei
Aging related loss of muscle maintenance and strength, referred to as sarcopenia, represents a major health problem in the elderly. The pathophysiology is still poorly understood and efficient therapies are lacking. The disease is linked to aging-associated metabolic changes and dietary therapies have long been searched for, but without success. Vitamin-A (VA) is an essential food component that regulates muscle growth during development via retinoic acid (RA) signaling. Its role in aging-related sarcopenia has not been explored. Here, we show that dietary depletion of VA has a profound capacity to prevent the development of aging associated sarcopenia in mice. This rescue is not induced by direct effects of VA-free diet (VAFD) on skeletal muscle as retinol plasma level and RA-signaling in the muscle remain unchanged under VAFD. Instead, VAFD leads to improvements in hepatic fat metabolism by inducing (i) PPAR-alpha-mediated transcriptional activation of lipid metabolism, (ii) reprogramming of chromatin accessibility of hepatocytes leading to silencing of inhibitory pathways of liver fat metabolism, and (iii) the secretion of FGF21 - a hepatokine activating glucose metabolism in peripheral organs. These hepatic effects of VAFD are linked to a rescue of biological hallmarks of muscle aging, including reduction in mitochondrial oxidative metabolism, overactivation of catabolic proteolysis, and impairments in the maintenance of proteins required for muscular contraction. Together, these findings provide experimental evidence that aging-associated impairments in liver fat metabolism are linked to the development of aging-associated sarcopenia. VAFD is identified as a powerful, dietary intervention, which prevents sarcopenia development by rescuing aging-associated impairments in liver fat metabolism. These findings could also have implications for the unexplained connection between the decline in hepatic fat metabolism in liver diseases (such as cirrhosis, NASH and NAFLD) and sarcopenia.