Circulating miR-4532 is associated with loss of ambulation in dysferlinopathy

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are inherited myopathies characterized mainly by progressive weakness of the proximal muscles of the shoulder and pelvic girdle areas, leading to functional decline and eventual loss of independent ambulation. Dysferlinopathy (LGMD2B) is an autosomal recessive LGMD subtype, is caused by mutations in the DYSF gene that lead to lack of dysferlin which results in muscle death and chronic muscle fiber degeneration. Preservation of ambulation is a key clinical milestone, as loss of independent gait markedly reduces quality of life and complicates care management. Although patients often perceive functional decline before their initial clinical presentation, current clinical assessments typically detect disease progression after substantial muscle damage has occurred. Methods In this multigroup case-control study, we profiled plasma miRNAs from 49 genetically confirmed dysferlinopathy patients (24 ambulatory, 25 non-ambulatory) and 25 age- and sex-matched healthy controls. Total RNA was extracted from blood samples and hybridized to Affymetrix GeneChip miRNA 3.1 arrays. After quality control and filtering, differential expression analysis was performed using linear models for microarrays, adjusting for age and sex, with a false discovery rate cutoff of 10%. Results 14 miRNAs were significantly altered between dysferlinopathy patients and controls. Notably, miR-4532 was upregulated in ambulatory patients relative to controls, whereas it was downregulated in non-ambulatory patients compared with ambulatory patients, although expression levels remained higher than in controls. Levels of miR-4532 were positively associated with circulating monocyte levels in ambulatory patients only. Conclusion These results suggest that miR-4532 may be a circulating marker associated with ambulatory status in dysferlinopathy. Its known involvement in inflammatory signaling and muscle regeneration pathways underscores its potential as an early indicator for disease activity.