Klotho Is Cardioprotective in the mdx Mouse Model of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal, progressive skeletal and cardiac myopathy. Cardiomyopathy is the leading cause of death in patients with DMD, but the molecular basis for heart failure is incompletely understood. As with humans, in the mdx mouse model of DMD, cardiac function is impaired after the onset of skeletal muscle pathology. Dysregulation of Klotho gene regulation in dystrophic skeletal muscles occurs at disease onset, affecting pathogenesis. Whether Klotho is protective against dystrophin-deficient cardiomyopathy is unknown. This study found that expression of a Klotho transgene prevented deficits in left ventricular ejection fraction and fractional shortening in mdx mice. Improvements in cardiac performance were associated with reductions in adverse cardiac remodeling, cardiac myocyte hypertrophy, and fibrosis. In addition, mdx mice expressed high concentrations of plasma fibroblast growth factor 23 (FGF23), and expression was increased locally in hearts. The cardioprotective effects of Klotho were not associated with differences in renal function or serum biochemistries, but transgene expression prevented increased expression of plasma FGF23 and cardiac Fgf23 mRNA expression. Cardiac reactive oxygen species, oxidative damage, mitochondrial damage, and apoptosis were reduced in transgenic hearts. FGF23 stimulated hypertrophic growth in dystrophic neonatal mouse ventricular myocytes in vitro, which was inhibited by co-stimulation with soluble Klotho. Taken together, these results show that Klotho prevented dystrophic cardiac remodeling and improved function.