Comprehensive Profiling of Annexins in Neuromuscular Disorders Reveals a Unique Signature in Dysferlinopathy

Background Annexins are a family of calcium‐dependent membrane‐binding proteins implicated in membrane repair and inflammation, yet their immunoreactivity patterns in neuromuscular disorders remain poorly characterized. This study systematically examined the immunoreactivity profiles of annexins A1, A2, A4, A5, A6, A7, and A11 across various muscular dystrophies, including muscular dystrophies, inflammatory myopathies, lipid storage myopathy (LSM), and amyotrophic lateral sclerosis (ALS). Methods Muscle biopsies from patients with dysferlinopathy, Duchenne/Becker muscular dystrophy (DMD/BMD), myotonic dystrophy type 1 (DM1), oculopharyngeal muscular dystrophy (OPMD), facioscapulohumeral muscular dystrophy (FSHD), LSM, inflammatory myopathies, and ALS, along with controls, were analyzed. Immunofluorescence and immunoblot assays were used to assess annexin localization and abundance, and quantitative immunoreactivity levels were statistically compared with controls. Results Dysferlinopathy showed a distinct upregulation of multiple annexins (A1, A2, A4, A5, A6, and A7). These annexins were primarily localized to the extracellular matrix, with additional cytoplasmic accumulation in atrophied fibers. Annexin A6 was strongly associated with the sarcolemma, while annexin A7 was diffusely distributed. In contrast, other myopathies such as OPMD and FSHD exhibited reduced or unchanged annexin immunoreactivity. Inflammatory myopathies partially mirrored the dysferlinopathy pattern, though annexin A2 levels were lower. ALS samples displayed minimal immunoreactivity, restricted to focal cytoplasmic annexin A1 and sparse sarcolemmal annexin A6. Conclusions These findings reveal a unique annexin signature in dysferlinopathy, suggesting a potential involvement in membrane repair and inflammatory modulation. The differential expression across disorders highlights the diverse roles of annexins in muscle pathophysiology and supports their utility as diagnostic biomarkers and therapeutic targets.