Immunoproteasome Inhibition Ameliorates Aged Dystrophic Mouse Muscle Environment

Area of Science:

• Biochemistry
• Immunology
• Muscle Physiology

Background:

• Duchenne muscular dystrophy (DMD) involves muscle wasting due to inflammation, oxidative stress, and senescence.
• The inducible proteasome (immunoproteasome, IP) plays a key role in these pathological processes.
• Previous studies showed IP inhibition benefits young DMD mice.

Purpose of the Study:

• To investigate the efficacy of ONX-0914, a selective IP inhibitor, in older (9-month-old) DMD model mice.
• To assess its impact on pathological traits contributing to muscle wasting progression.

Main Methods:

• Treatment of 9-month-old mdx mice (DMD model) with ONX-0914.
• Analysis of immune cell populations (macrophages, T cells) in muscle and spleen.
• Assessment of inflammatory markers, oxidative stress, mitochondrial function, fibrosis, and myofiber regeneration.

Main Results:

• ONX-0914 reduced macrophages and effector memory T cells, increasing regulatory T cells.
• It modulated inflammatory markers in skeletal and cardiac muscle, potentially mitigating heart issues.
• The treatment improved mitochondrial efficiency, buffered oxidative stress, decreased fibrosis, and controlled myofiber turnover.

Conclusions:

• ONX-0914 ameliorates key pathological features driving muscle wasting in advanced-stage DMD models.
• It shows potential for slowing muscle mass loss in DMD patients with moderate to advanced disease with manageable side effects.