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Updated: May 2, 2026
Assessing Functional Performance in the Mdx Mouse Model
Published on: March 27, 2014
Klotho Is Cardioprotective in the mdx Mouse Model of Duchenne Muscular Dystrophy
Areli Jannes S Javier1, Felicia M Kennedy2, Xin Yi2
1Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana.
Insights
Klotho protects against heart failure in Duchenne muscular dystrophy (DMD). This study shows Klotho prevents cardiac remodeling and improves heart function in mdx mice, offering a potential therapeutic target for DMD cardiomyopathy.
Area of Science:
- Biochemistry
- Genetics
- Cardiology
Background:
- Duchenne muscular dystrophy (DMD) causes progressive skeletal and cardiac myopathy, with cardiomyopathy being the primary cause of death.
- The molecular mechanisms underlying heart failure in DMD are not fully understood.
- Klotho gene dysregulation occurs in DMD skeletal muscles, but its role in cardiac pathology is unknown.
Purpose of the Study:
- To investigate the protective role of Klotho against dystrophin-deficient cardiomyopathy in the mdx mouse model.
- To determine the effects of Klotho on cardiac function, remodeling, and associated molecular pathways in DMD.
Main Methods:
- Expression of a Klotho transgene in mdx mice.
- Assessment of cardiac function (ejection fraction, fractional shortening).
- Analysis of cardiac remodeling markers (hypertrophy, fibrosis), FGF23 levels, oxidative stress, and apoptosis.
- In vitro studies using neonatal mouse ventricular myocytes.
Main Results:
- Klotho transgene expression prevented deficits in left ventricular ejection fraction and fractional shortening in mdx mice.
- Improvements in cardiac performance were linked to reduced cardiac remodeling, myocyte hypertrophy, and fibrosis.
- Klotho prevented elevated plasma FGF23 and cardiac Fgf23 mRNA expression, and reduced cardiac oxidative stress and apoptosis.
- FGF23 promoted hypertrophic growth in vitro, which was inhibited by Klotho.
Conclusions:
- Klotho demonstrates significant cardioprotective effects in the context of Duchenne muscular dystrophy.
- Klotho prevents dystrophic cardiac remodeling and improves cardiac function, potentially by modulating FGF23 signaling and oxidative stress.
- These findings highlight Klotho as a potential therapeutic target for DMD-associated cardiomyopathy.
Abstract:
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.
