Immunoproteasomes in Skeletal Muscle Pathologies: Emerging Roles, Conflicting Evidence, and Future Directions.

Area of Science:

• Muscle physiology and immunology
• Protein degradation pathways
• Inflammatory disease mechanisms

Background:

• Skeletal muscle pathologies like sarcopenia and muscular dystrophies involve chronic inflammation and poor protein quality control.
• Immunoproteasomes (IMPs) are key regulators linking immune responses to protein homeostasis in muscle.
• IMPs exhibit dual roles: supporting muscle repair under stress but potentially driving inflammation and wasting when persistently active.

Purpose of the Study:

• To review the current understanding of immunoproteasome roles in skeletal muscle pathologies.
• To highlight the paradoxical functions and controversies surrounding IMP inhibition in muscle disease.
• To identify knowledge gaps and suggest future research directions for therapeutic strategies.

Main Methods:

• Literature review of preclinical and clinical studies on immunoproteasomes in skeletal muscle.
• Analysis of evidence regarding IMP function in inflammation, proteostasis, and muscle regeneration.
• Examination of the effects of selective IMP inhibitors (e.g., ONX 0914, KZR-616) in disease models.

Main Results:

• IMPs can be beneficial for muscle regeneration but may promote chronic inflammation and muscle wasting upon sustained activation.
• Selective IMP inhibitors show anti-inflammatory effects but raise concerns about impairing muscle repair and proteostasis.
• The therapeutic utility of IMP inhibitors in skeletal muscle diseases is context-dependent and debated.

Conclusions:

• A deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology is crucial.
• Targeting IMPs presents both therapeutic promise and potential risks, necessitating context-specific strategies.
• Future research should focus on balancing beneficial anti-inflammatory effects with potential adverse impacts on muscle function and repair.