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

## TL;DR

Deleting the C9ORF72 gene in mice causes muscle fiber shrinkage and mitochondrial issues, suggesting it's important for muscle health and may contribute to ALS.

## Contribution

This study reveals C9ORF72's role in maintaining muscle protein and mitochondrial balance in skeletal muscle.

## Key findings

- C9ORF72 deletion reduces large muscle fibers and increases proteasomal and autophagic activity.
- Loss of C9ORF72 disrupts mitophagy and causes mitochondrial structural abnormalities.
- C9ORF72 is critical for maintaining proteostasis and mitochondrial integrity in skeletal muscle.

## Abstract

What are the main findings?
Deletion of C9ORF72 in mice results in a significant reduction in large muscle fibers, accompanied by increased proteasomal and autophagic activity.Loss of C9orf72 in skeletal muscle disrupts mitophagy and leads to ultrastructural mitochondrial abnormalities.

Deletion of C9ORF72 in mice results in a significant reduction in large muscle fibers, accompanied by increased proteasomal and autophagic activity.

Loss of C9orf72 in skeletal muscle disrupts mitophagy and leads to ultrastructural mitochondrial abnormalities.

What are the implications of the main findings?
C9ORF72 plays a critical role in maintaining mitochondrial integrity and proteostatic balance in skeletal muscle.Although C9ORF72 loss of function does not produce overt muscle weakness, it may render muscle fibers more vulnerable to degeneration in C9orf72-linked ALS.

C9ORF72 plays a critical role in maintaining mitochondrial integrity and proteostatic balance in skeletal muscle.

Although C9ORF72 loss of function does not produce overt muscle weakness, it may render muscle fibers more vulnerable to degeneration in C9orf72-linked ALS.

The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.