C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• C9ORF72 mutations are a primary genetic cause of amyotrophic lateral sclerosis (ALS).
• While neuronal and immune roles are known, C9ORF72's impact on skeletal muscle in ALS is poorly understood.
• Skeletal muscle pathology is a hallmark of C9ORF72-linked ALS.

Purpose of the Study:

• To investigate the effects of C9ORF72 deficiency on skeletal muscle structure and function.
• To elucidate the molecular mechanisms underlying muscle changes in C9ORF72-related ALS.

Main Methods:

• Analysis of skeletal muscle from C9ORF72 knockout mice.
• Performed Western blotting, microscopy, and molecular assessments.
• Evaluated muscle fiber size, composition, mitochondrial morphology, and protein degradation pathways.

Main Results:

• Observed reduced large muscle fibers (19.5%) and altered fiber composition.
• Identified mitochondrial abnormalities (smaller size, altered cristae) and impaired quality control (increased PINK1, decreased Parkin, PGC-1α).
• Detected increased proteasomal degradation (Atrogin-1) and enhanced autophagy (LC3BII/LC3BI, Beclin-1, reduced p62).

Conclusions:

• C9ORF72 is essential for maintaining skeletal muscle protein and mitochondrial homeostasis.
• C9ORF72 deficiency impairs mitochondrial function and promotes protein degradation.
• While not causing overt weakness in mice, C9ORF72 deficiency may predispose skeletal muscle to vulnerability in ALS.