Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate

Peroxisome proliferator-activated receptor-? coactivator-1a (PGC-1a) is a master regulator of mitochondrial biogenesis. Reduced PGC-1a abundance is linked to skeletal muscle weakness in aging or pathological conditions; thus, elevating PGC-1a abundance might be a promising strategy to treat muscle aging. Here we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1a. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farensol treatment accelerated the recovery of muscle injury associated with enhanced muscle stem cell function. The protein expression of Parkin-interacting substrate (PARIS/Zfp746), a transcriptional repressor of PGC-1a, was elevated in aged muscles, likely contributing to PGC-1a reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1a suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS farnesylation in the muscles of aged mice, leading to the elevation of PGC-1a. Collectively, the current study demonstrated that the PARIS-PGC-1a pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS. Overall design: To further investigate the effect of farnesol in aged muscles, RNA-sequencing analysis was performed on GAS muscles from vehicle (V)- or farnesol (F)-fed 26-month-old mice. Farnesol is orally administrated for 30 days. Then, we harvested gastrocnemius (GAS) muscles and performed RNA-sequencing using isolated total RNA.