In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction

Introduction: Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of Peroxisome Proliferator-activated Receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.

Objectives: This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.

Methods: We analyzed age-stratified muscle transcriptome datafrom various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. In silico transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol's efficacy and mechanisms were assessed through histological analysis, Molecular Biology, and transcriptomics analysis.

Results: Celastrol, a bioactive triterpenoid from Tripterygium wilfordii Hook. F., was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.

Conclusion: Collectively, these findings suggest celastrol as apharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.

CMap; Celastrol; Mitochondria; Myogenic differentiation; PGC-1α; Sarcopenia.