Foxo/atrogin induction in human and experimental myositis.

Area of Science:

• Muscle physiology and disease
• Molecular biology of protein degradation
• Neuroimmunology

Background:

• Skeletal muscle atrophy is a significant issue in various catabolic and inflammatory conditions.
• The ubiquitin ligase Atrogin-1 (MAFbx) is known to induce myoprotein degradation in animal models.
• Its role in acquired human myopathies like Inclusion Body Myositis (IBM) and Polymyositis (PM) remained unclear.

Purpose of the Study:

• To investigate the role of Atrogin-1 in human myositis (sIBM and PM).
• To explore the molecular mechanisms linking intracellular beta-amyloid (Aβi) and inflammation to muscle atrophy.
• To determine if these pathways converge on the Foxo transcription factor.

Main Methods:

• Analysis of Atrogin-1 and Foxo3A expression in human myositis patient samples.
• Utilizing transgenic mouse models expressing Aβ.
• Employing differentiated C2C12 myotubes to study Aβi effects.
• Investigating a mouse model of autoimmune myositis.

Main Results:

• Atrogin-1 transcript and nuclear Foxo3A were increased in both sIBM and PM.
• Aβ expression upregulated Atrogin-1 mRNA and induced atrophy in mice and myotubes.
• Aβi reduced p-Akt and p-Foxo3A, leading to Foxo3A nuclear translocation and Atrogin-1 induction.
• Cellular inflammation in a mouse model showed similar Foxo3A and Atrogin changes.

Conclusions:

• Both intracellular Aβ accumulation and cellular immune stimulation can independently drive muscle atrophy in sIBM and PM.
• These pathways converge on the Foxo/Atrogin-1 axis.
• In sIBM, a synergistic effect of both mechanisms is possible, exacerbating muscle wasting.