PGC-1α buffers ROS-mediated removal of mitochondria during myogenesis

Area of Science:

• Cellular Biology
• Mitochondrial Biology
• Muscle Physiology

Background:

• Mitochondrial homeostasis is crucial, involving biogenesis and mitophagy.
• The molecular mechanisms balancing these processes, especially during myogenesis, remain unclear.

Purpose of the Study:

• To investigate the role of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) in coordinating mitochondrial homeostasis during muscle differentiation.
• To elucidate the molecular pathways linking PGC-1α, oxidative stress, and mitophagy.

Main Methods:

• Studied PGC-1α expression during myogenesis in myotubes.
• Manipulated PGC-1α levels and assessed mitochondrial gene expression, antioxidant enzyme activity, and reactive oxygen species (ROS) levels.
• Investigated the ROS/FOXO1 pathway, including FOXO1 nuclear translocation and the expression of mitophagy-related genes (LC3, PINK1).
• Evaluated mitochondrial mass, function, and muscle-specific gene expression (MYOG, FBXO32) following PGC-1α modulation and antioxidant treatment (Trolox).

Main Results:

• PGC-1α is induced during myogenesis, co-activating nuclear and mitochondrial gene transcription.
• PGC-1α down-regulation impairs antioxidant expression, leading to ROS burst, oxidative damage, decreased mitochondrial mass/function, and increased mitophagy via ROS/FOXO1 pathway.
• ROS-dependent nuclear translocation of FOXO1 and transcription of mitophagy genes (LC3, PINK1) were observed upon PGC-1α downregulation, effects reversed by Trolox.
• Lack of PGC-1α reduced MYOG expression and induced atrophy-related gene FBXO32.

Conclusions:

• PGC-1α is central to mitochondrial homeostasis in differentiating myotubes.
• PGC-1α maintains mitochondrial integrity by buffering ROS, thereby preventing excessive mitophagy and muscle atrophy.
• The findings highlight PGC-1α's critical role in muscle differentiation and preventing degenerative processes.