Inflammation in a severe model of dystrophic cardiomyopathy contains a high proportion of T cells that contribute to onset of pathology.

Abstract

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder with progressive muscle degeneration and cardiomyopathy leading to heart failure. The inflammatory environment in dystrophic skeletal muscle is well-studied, but little is known about inflammation in DMD cardiomyopathy due to the lack of adequate animal models. We recently developed the Fiona/dko mouse model, deficient for both dystrophin and utrophin, but containing a skeletal muscle-specific expressing utrophin transgene allowing progression of dystrophic cardiomyopathy. This Fiona/dko model is the first DMD cardiomyopathy model to reproducibly progress to reduced cardiac contractile function by 9 mo. In this study, we compared immune cell composition between Fiona/dko mice and their milder littermates that develop cardiac pathology, but do not demonstrate whole heart dysfunction. Flow cytometry analysis revealed that T cells constitute a significant proportion of the immune cell population in dystrophic hearts, in contrast to the known predominantly myeloid signature in dystrophic skeletal muscles. T cell infiltration precedes the development of cardiac fibrosis and dysfunction in Fiona/dko mice. RNA sequencing of whole hearts after cardiac dysfunction shows increased expression of 68 genes related to T cell signaling in Fiona/dko compared with their milder littermates. Furthermore, depletion of circulating CD3T cells with a neutralizing antibody ameliorates early pathology in Fiona/dko hearts. Together, these data suggest a role for T cells in the initiation and persistence of dystrophic cardiomyopathy. These findings highlight the distinct inflammatory environment in the dystrophic heart and provide new insights into DMD cardiomyopathy, paving the way for the future development of targeted anti-inflammatory therapies.Heart failure has become the leading cause of death in Duchenne muscular dystrophy, a progressive degenerative disease of striated muscles. This study highlights an inflammatory environment in dystrophic heart with a high proportion of T-cells that is distinct from the predominant myeloid inflammation in dystrophic skeletal muscles. T-cell-related signaling is associated with the severity of cardiomyopathy, and T-cells contribute to dystrophic cardiomyopathy onset. This data will inform optimal patient treatments that target cardiac inflammation.