27-Hydroxycholesterol inhibits muscle cell viability via mitochondrial dysfunction: Protective role of ROS-induced...

Area of Science:

• Biochemistry
• Molecular Biology
• Muscle Physiology

Background:

• Oxysterol 27-hydroxycholesterol (27OHC) is implicated in various pathologies, but its role in muscle pathophysiology, particularly sarcopenia, is unclear.
• Sarcopenia and muscle atrophy are age-related conditions significantly impacting health and mobility.

Purpose of the Study:

• To investigate the effects of 27OHC on skeletal muscle viability, cellular pathways, and in vivo muscle function.
• To explore the potential of targeting 27OHC for therapeutic interventions against age-related muscle loss.

Main Methods:

• Utilized myoblast cell culture treated with 27OHC, followed by RNA sequencing and analysis of apoptotic and mitochondrial pathways.
• Assessed reactive oxygen species (ROS) generation, mitochondrial membrane potential, and gene expression related to muscle differentiation.
• Evaluated in vivo effects in mice, including exercise endurance, muscle morphology, and injury recovery after 27OHC administration.

Main Results:

• 27OHC decreased myoblast viability by activating pro-apoptotic pathways and inducing ROS, leading to mitochondrial dysfunction.
• RNA sequencing revealed significant upregulation of hypoxia-inducible factor 1-alpha (HIF-1α) response genes and downregulation of pathways crucial for muscle differentiation and PI3K signaling.
• 27OHC treatment in mice resulted in reduced exercise capacity, smaller muscle size, and impaired muscle regeneration, correlating with increased plasma 27OHC levels in elderly individuals.

Conclusions:

• 27OHC directly impairs skeletal muscle cells, contributing to muscle atrophy and sarcopenia through apoptosis and disrupted differentiation.
• HIF-1α activation and mitochondrial dysfunction are key mechanisms underlying 27OHC-induced muscle damage.
• Pharmacological inhibition of 27OHC production presents a potential therapeutic strategy for combating age-related muscle decline.