Welc Lab

Macrophages (green) closely associated with regenerating fibers (purple) in dystrophin-deficient skeletal muscle.

Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by genetic mutations to the dystrophin gene. Without dystrophin the mechanical infrastructure of striated muscle cells is compromised causing destabilization of the muscle cell membrane and cellular necrosis. While membrane fragility contributes to the pathophysiology of DMD, it alone cannot account for many pathological features of the disease. The pathophysiology of dystrophin-deficiency is intertwined with multiple secondary defects, including perturbations in the epigenetic regulation of gene expression, as well as considerable involvement of other tissues such as the immune system and stromal cells. Patients could benefit from effective countermeasures that target events downstream of dystrophin-deficiency. Our findings have shown that ⍺Klotho is epigenetically silenced in dystrophic muscles at the onset of dystrophinopathy and that restoring ⍺Klotho expression systemically or via infiltrating bone marrow-derived cells improves regeneration and function. Ongoing investigations, supported by the Muscular Dystrophy Association, are aimed at investigating the mechanisms through which restoring ⍺Klotho reduces fibrosis in dystrophic muscles.

Other investigations in our lab include exploring the molecular mechanisms controlling the differentiation muscle mesenchymal cells (Fibro/adipogenic progenitors) and pathological fibrosis in dystrophin-deficient muscles, supported by Ralph W. and Grace M. Showalter Research Trust. The laboratory is also exploring mechanisms through which fibroblasts could promote cardiac myocyte injury, hypertrophy and remodeling in the dystrophin-deficient heart.

Pathological remodeling of the dystrophin-deficient myocardium (right).

Inflammatory lesion in injured muscle featured on the cover of The Journal of Immunology (Vol. 205, Issue 6. DOI: 10.4049/jimmunol.2000247)

A major goal of the laboratory is to understand the regulatory interactions between the immune system and skeletal muscle that are important in regulating muscle regeneration. In recent years, appreciation for the contributions of myeloid cells to the regeneration of injured muscle has grown. However, our understanding of the molecular mechanisms that activate macrophages to a pro-regenerative phenotype and the specific soluble factors produced by macrophages to facilitate regeneration is incomplete. We are attempting to understand the signaling pathways that activate macrophages to an M2-biased pro-regenerative phenotype. Using a mouse line in which there is a targeted deletion of PPARδ in myeloid cells we determined that PPARδ regulates the recruitment of macrophages to injured muscle but did not reduce the expression of phenotypic markers associated with M2 macrophage activation. These findings are distinct from other notable investigations that demonstrated the importance of PPARδ expression and activation in regulating the phenotype of liver- and adipose tissue-resident macrophages and suggest that the mechanisms that regulate M2-biased macrophage activation differ in different in vivo environments. The lab is also interested in the activation of muscle macrophages to non-canonical phenotypes in muscular dystrophy and with aging, as well as potential maladaptive consequences to muscle health.