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

Ju-Hyeon BaeAreum JoSung Chun ChoYun-Il LeeTae-In KamChang-Lim YouHyeon-Ju JeongHyebeen KimMyong-Ho JeongYideul JeongYoung Wan HaYu Seon KimJiwoon KimSeung-Hwa WooMinseok S KimEui Seok ShinSang Ok SongHojin KangRin KhangSoojeong ParkJoobae ParkValina L DawsonTed M DawsonSang Chul ParkJoo-Ho ShinJong-Sun Kang
Published in: Science translational medicine (2023)
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α 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-1α. Farnesol administration enhanced oxidative muscle capacity and muscle strength, leading to metabolic rejuvenation in aged mice. Moreover, farnesol 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-1α, was elevated in aged muscles, likely contributing to PGC-1α reduction. The beneficial effect of farnesol on aged muscle was mediated through enhanced PARIS farnesylation, thereby relieving PARIS-mediated PGC-1α suppression. Furthermore, short-term exercise increased PARIS farnesylation in the muscles of young and aged mice, whereas long-term exercise decreased PARIS expression in the muscles of aged mice, leading to the elevation of PGC-1α. Collectively, the current study demonstrated that the PARIS-PGC-1α pathway is linked to muscle aging and that farnesol treatment can restore muscle functionality in aged mice through increased farnesylation of PARIS.
Keyphrases
  • skeletal muscle
  • insulin resistance
  • candida albicans
  • high fat diet induced
  • type diabetes
  • physical activity
  • oxidative stress
  • metabolic syndrome
  • adipose tissue
  • mouse model
  • microbial community