Forskolin treatment enhances muscle regeneration and shows therapeutic potential with limitations in Duchenne muscular dystrophy

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BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder characterized by impaired muscle repair. Forskolin (FSK), an adenylyl cyclase activator, has shown potential in enhancing muscle regeneration and limiting muscle stem cell senescence. This study aimed to evaluate the effects of FSK on muscle repair, fibrosis, inflammation, and long-term muscle function in DMD using a preclinical rat model. METHODS: -induced muscle injury was performed on 6-month-old DMD (R-DMDdel52) and wild-type (WT) rats. FSK was supplied via short-term and long-term administration. Muscle tissues were harvested 14 days post-injury for histological analysis, including hematoxylin and eosin and Sirius red staining. Immunofluorescence was used to assess fibroadipogenic progenitors (FAPs), regeneration, muscle stem cells, and macrophage phenotypes. Moreover, we performed a study by chronically administering FSK to DMD rats from 1 to 7 months of age, either intraperitoneally (IP) or subcutaneously (SC). Functional assessments included grip strength test, in vivo muscle force measurements, plethysmography and electrocardiograms. Post-sacrifice, Tibialis anterior, diaphragm and heart tissues were histologically analyzed, to evaluate muscle architecture, fibrosis, and histopathological indices. RESULTS: FSK treatment significantly improved muscle histology and reduced fibrosis in both uninjured and injured DMD muscles by decreasing the number of FAPs. Long-term FSK treatment in the acute injury model enhanced muscle regeneration, increased MuSC proliferation, and reduced senescence. FSK also modulated inflammation by reducing pro-inflammatory macrophages and promoting a shift to a restorative phenotype. However, despite these histological improvements, FSK treatment from 1 to 7 months resulted in limited functional benefits and worsened ventricular histology in the heart. CONCLUSIONS: FSK shows promising results in improving muscle regeneration and reducing fibrosis in DMD, but concerns remain regarding its limited chronic functional benefits and potential adverse effects on cardiac tissue. Our results highlight the need for optimized adenylyl cyclase activators for therapeutic use in DMD patients.

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