Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by the lack of the structural protein dystrophin. Despite the common genetic basis, genetic modifiers that alter extracellular signaling and extracellular matrix lead to different disease severity and prognosis between patients. The D2-mdx mouse is a severe DMD model that carries a polymorphism in the LTBP4 gene leading to higher TGF-beta activity and excessive fibrosis. Heightened TGF-beta activity in D2-mdx mice promotes fibro-calcification of the muscle even in the juvenile mouse and we have shown that the juvenile D2-mdx muscles also fail to regenerate. Excessive fibrosis and failed regeneration would lead to loss of affected muscles by adulthood, but this does not appear to be the case. While the adult D2-mdx muscle show increased fibrosis, we find the extent of damaged muscle is reduced and is comparable to levels in the less severe B10-mdx adult mice. Extent of FAP and macrophage accumulation in sites of active muscle damage is also reduced in adult D2-mdx muscle. We find these improvements in the adult D2-mdx muscle are associated with the increased capacity of the adult D2-mdx muscle to regenerate, at levels seen in the B10-mdx model. Above features of D2-mdx muscle can be recapitulated by muscle injury in juvenile and adult D2-WT mice. Poor regeneration of juvenile D2-mdx mouse muscles is associated with multiple asynchronously damaged areas in the muscle with the damage sites exhibiting altered inflammatory response when compared to juvenile B10-mdx. This is reversed in adult D2-mdx muscles that do not manifest asynchronous injuries. We will discuss the utility of approaches that reverse this aberrant inflammatory response in improving regenerative myogenesis in the D2-mdx muscles and the impact of such an approach for treating myogenic deficit in the DMD patients.