Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation

Area of Science:

• Cell Biology
• Skeletal Muscle Physiology
• Mitochondrial Dynamics

Background:

• Mitochondrial fission and fusion are vital for skeletal muscle function.
• Previous in vivo studies on mitochondrial fission's role in muscle development were limited by early model lethality.

Purpose of the Study:

• To investigate the role of mitochondrial fission in skeletal muscle development and repair.
• To generate a transgenic mouse model for studying Drp1-induced mitochondrial fission in skeletal muscle.

Main Methods:

• Generation of a transgenic mouse line overexpressing the fission-inducing protein Drp1 specifically in skeletal muscle.
• Analysis of postnatal muscle growth, mitochondrial network organization, mtDNA quantity, and bioenergetics.
• Investigation of the PKR/eIF2α/Fgf21 pathway activation and its impact on protein synthesis and growth hormone signaling.

Main Results:

• Drp1 overexpression led to significant impairment in postnatal muscle growth.
• Mice exhibited mitochondrial network reorganization and reduced mtDNA quantity, but maintained mitochondrial bioenergetics.
• Drp1 overexpression activated the PKR/eIF2α/Fgf21 pathway, attenuating protein synthesis and downregulating the growth hormone pathway.

Conclusions:

• Mitochondrial network dynamics, specifically fission, critically influence muscle growth and development.
• The findings reveal a novel mechanism linking mitochondrial stress responses to muscle growth regulation.
• This study provides insights into muscle physiology relevant to human muscle pathologies.