GDF15 Neutralization Ameliorates Muscle Atrophy and Exercise Intolerance in a Mouse Model of Mitochondrial Myopathy

Area of Science:

• Mitochondrial Biology
• Muscle Physiology
• Therapeutic Antibody Development

Background:

• Primary mitochondrial myopathies (PMMs) result from genetic defects affecting mitochondrial function, leading to muscle atrophy and reduced exercise capacity.
• Elevated Growth/Differentiation Factor 15 (GDF15) levels are observed in PMMs and cancer cachexia, suggesting its role in muscle wasting.
• GDF15 neutralization has shown efficacy in cancer cachexia, but its therapeutic potential in PMMs remains unexplored.

Purpose of the Study:

• To investigate the efficacy of GDF15 neutralization using a monoclonal antibody in a mouse model of PMM.
• To assess the impact of anti-GDF15 treatment on muscle atrophy and physical performance impairments.

Main Methods:

• Utilized Polg^D257A/D257A (POLG) mice, which exhibit PMM-like phenotypes including elevated GDF15, muscle loss, and exercise intolerance.
• Administered an anti-GDF15 antibody (mAB2) weekly for 12 weeks to 9-month-old POLG mice.
• Assessed body composition, muscle mass, muscle function (max force production), and exercise capacity (treadmill, voluntary wheel running). Mechanistic studies included histology, transcriptomics, RT-qPCR, and western blotting.

Main Results:

• Anti-GDF15 treatment significantly improved body weight, lean mass, and muscle mass in POLG mice.
• Skeletal muscle force production and exercise performance (treadmill and voluntary wheel running) were substantially enhanced.
• Mechanistically, treatment reversed transcriptional dysregulation in autophagy and proteasome signaling pathways and reduced corticosterone levels.

Conclusions:

• GDF15 neutralization with a monoclonal antibody demonstrates significant therapeutic potential for PMM.
• This approach can enhance physical performance and mitigate adverse clinical outcomes in PMM patients.
• Targeting GDF15 offers a promising therapeutic strategy for primary mitochondrial myopathies.