T.P.5 Sildenafil (Viagra®) improves cardiac and diaphragm muscle function in the dystrophic mouse

Abstract Until genetic correction approaches are routinely available for treatment of muscular dystrophies, treatments that extend longevity and improve quality of life will be important alternatives. Based on our studies of one isoform of nitric oxide synthase (nNOSβ) which localizes on the Golgi with guanylyl cyclase and protein kinase G, we proposed that increasing cGMP levels by inhibition of specific phosphodiesterases (PDEs) would improve cardiac and skeletal muscle function in the mdx mouse. We examined the effect of sildenafil (Viagra), a selective inhibitor of PDE5 which is present in cardiac and diaphragm muscle. Our published results (Adamo et al., 2010, Proc. Natl. Acad. Sci. 107:19079) showed that chronic administration of sildenafil via the drinking water reduces functional deficits in the cardiac performance of aged mdx mice. Furthermore, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were reversed within a few days. Chronic administration of sildenafil to mdx mice beginning at 3 weeks of age improved diaphragm function. At 5 months of age, diaphragms from mdx mice treated with sildenafil exhibited less Evans Blue dye uptake and markedly reduced levels of fibrosis, compared to untreated mdx diaphragms. Functional measurements showed an increase in specific force. Quantitative PCR analyses of pro-fibrotic and pro-inflammatory gene expression revealed that transcript levels for TNFα and MMP-13 were upregulated in dystrophic diaphragm. Sildenafil treatment reduced the transcripts of TNFα and MMP-13 to near normal levels. Our results suggest that sildenafil treatment of individuals with muscular dystrophies and other muscle fibrotic diseases may preserve muscle function and integrity.