Apoptosis repressor with a CARD domain (ARC) restrains Bax-mediated pathogenesis in dystrophic skeletal muscle

Area of Science:

• Cellular biology
• Molecular mechanisms of disease
• Muscle physiology

Background:

• Skeletal muscle wasting in muscular dystrophy is often attributed to necrosis.
• However, apoptotic markers have been observed in dystrophic muscles, suggesting a role for programmed cell death.

Purpose of the Study:

• To investigate the contribution of canonical apoptotic pathways to skeletal muscle degeneration in muscular dystrophy.
• To determine the role of apoptosis repressor with a CARD domain (Arc) in dystrophic muscle pathology.

Main Methods:

• Genetic deletion of the apoptosis repressor with a CARD domain (Arc/Nol3) in dystrophic mouse models (Sgcd and Lama2 null backgrounds).
• Assessment of skeletal muscle pathology, muscle performance, and caspase-independent cell death pathways.
• Mitochondria permeability transition pore (MPTP) inhibition using Debio-025.
• Analysis of Bax and Bak protein levels and mitochondrial morphology.
• Arc knockdown in mouse embryonic fibroblasts and assessment of cell death sensitivity.

Main Results:

• Nol3 (Arc) genetic deletion exacerbated skeletal muscle pathology and decreased muscle performance in dystrophic mice.
• The enhanced pathology was caspase-independent but dependent on the MPTP.
• Arc deficiency led to elevated Bax protein levels and increased mitochondrial swelling, indicating Arc restrains Bax-mediated cell death.
• Arc knockdown increased cell death sensitivity in fibroblasts, which was blocked in Bax/Bak1 double null cells.

Conclusions:

• Arc deficiency exacerbates muscular dystrophy pathogenesis.
• This exacerbation is mediated by a Bax-dependent sensitization of mitochondria-dependent cell death pathways.
• Arc plays a protective role in skeletal muscle by restraining pro-apoptotic factors like Bax.