Muscle transcriptomics of alpha-sarcoglycanopathy highlights inflammatory pathways driving disease.

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• Muscular dystrophies involve inflammation, impairing muscle regeneration and causing fibrosis.
• Sarcoglycanopathies, a type of limb-girdle muscular dystrophy (LGMD), have poorly understood inflammatory roles, especially in alpha-sarcoglycanopathy (LGMDR3).

Purpose of the Study:

• To characterize skeletal muscle and peripheral inflammatory signatures in LGMDR3 patients.
• To correlate inflammation with disease severity in LGMDR3.
• To compare LGMDR3 immune profiles with unaffected individuals and Sgca-null mice.

Main Methods:

• Bulk RNA sequencing of muscle biopsies from LGMDR3 patients and controls.
• Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs).
• Classification of patients into mild and severe groups based on SGCA expression.

Main Results:

• Severe LGMDR3 showed distinct gene expression profiles, with upregulated innate immune and T-cell activation pathways.
• Higher inflammatory infiltrate, M1 macrophages, and pro-inflammatory chemokines were found in severe LGMDR3.
• Increased CD8+, TH1 CD4+ lymphocytes, and activated monocytes were observed in LGMDR3 patients compared to controls.

Conclusions:

• Inflammation plays a significant role in the pathogenesis of severe LGMDR3.
• Distinct immune signatures differentiate severe from mild LGMDR3 cases.
• Findings support the development of targeted anti-inflammatory therapies for severe LGMDR3.