Dysferlinopathy Promotes an Intramuscle Expansion of Macrophages with a Cyto-Destructive Phenotype.

Dysferlinopathies are a group of muscular dystrophies resulting from a genetic deficiency in Dysf. Macrophages, highly plastic cells that mediate tissue repair and destruction, are prominent within dystrophic skeletal muscles of dysferlinopathy patients. We hypothesized that Dysf-deficient muscle promotes recruitment, proliferation, and skewing of macrophages toward a cyto-destructive phenotype in dysferlinopathy. To track macrophage dynamics in dysferlinopathy, we adoptively transferred enhanced green fluorescent protein-labeled monocytes into Dysf-deficient BLA/J mice with age-related (2 to 10 months) muscle disease and Dysf-intact (C57BL/6 [B6]) mice. We detected an age- and disease-related increase in monocyte recruitment into Dysf-deficient muscles. Moreover, macrophages recruited into muscle proliferated locally and were skewed toward a cyto-destructive phenotype. By comparing Dysf-deficient and -intact monocytes, our data showed that Dysf in muscle, but not in macrophages, mediate intramuscle macrophage recruitment and proliferation. To further elucidate macrophage mechanisms related to dysferlinopathy, we investigated in vitro macrophage-myogenic cell interactions and found that Dysf-deficient muscle i) promotes macrophage proliferation, ii) skews macrophages toward a cyto-destructive phenotype, and iii) is more vulnerable to macrophage-mediated apoptosis. Taken together, our data suggest that the loss of Dysf expression in muscle, not macrophages, promotes the intramuscle expansion of cyto-destructive macrophages likely to contribute to dysferlinopathy. Identifying pathways within the Dysf-deficient muscle milieu that regulate cyto-destructive macrophages will potentially uncover therapeutic strategies for dysferlinopathies.