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Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe
Lili Salinas1, Francisco Figueroa1, Claire B Montgomery1
1Department of Molecular Biosciences University of California Davis CA USA.
Background:
Friedreich's ataxia (FA) is a genetic disorder caused by a severe decrease in FXN (frataxin) protein expression in mitochondria. The clinical manifestation of this disorder is a cerebellar ataxia; however, the common lethal component in FA is cardiomyopathy.
Methods:
A conditional Fxnflox/null::MCK-Cre knockout (FXN-cKO) mouse model was used to mimic the late-stage severe cardiomyopathy in FA. Nrf2 (nuclear factor erythroid 2-related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), were independently tested in this mouse model to determine the effects on cardiac health and lifespan.
Results:
Omaveloxolone significantly improved cardiac contractile function and markers of heart failure in FA such as Nppb, Aldh1a3, and Gdf15. Despite improvement in cardiac function, omaveloxolone did not prevent premature death in FXN-cKO animals and notably accelerated death in FXN-cKO females. Omaveloxolone decreased oxidative stress and inflammatory marker IL1β (interleukin-1 beta), and stimulated Nqo1 gene expression above control level. DMF restored elevated HO-1 (Hmox) expression and significantly increased Sirt1 expression. Although both omaveloxolone and DMF restored decreased SERCA2 (Atp2a) and MCU (Mcu) expression and ameliorated elevated phosphorylation of CaMKIIδ at Thr286 site in FA hearts, DMF did not improve cardiac contractile function and survival. Furthermore, neither omaveloxolone or DMF decreased hypertrophy and fibrosis (Masson trichrome staining and Lgals3 expression) or rescued impaired mitochondrial function and integrative stress response in FXN-cKO hearts.
Conclusions:
These data demonstrate that omaveloxolone significantly improved contractile function but not survival in FA hearts because cardiac fibrosis and wall stress persisted even with omaveloxolone treatment. More studies are warranted to determine the cause of premature death in omaveloxolone-treated FXN-cKO female mice.
Insights
Omaveloxolone improved cardiac function in Friedreich's ataxia (FA) mouse models but did not increase lifespan, with some models showing accelerated death. Further research is needed to understand treatment efficacy and mortality causes in FA cardiomyopathy.
Area of Science:
- Mitochondrial disease research
- Cardiovascular pathology in genetic disorders
- Pharmacological interventions for rare diseases
Background:
- Friedreich's ataxia (FA) is a genetic disorder characterized by reduced mitochondrial frataxin (FXN) protein.
- While FA causes cerebellar ataxia, cardiomyopathy is the primary lethal complication.
- A conditional FXN knockout mouse model (FXN-cKO) replicates severe FA cardiomyopathy.
Purpose of the Study:
- To evaluate the efficacy of Nrf2 (nuclear factor erythroid 2-related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), in an FA cardiomyopathy mouse model.
- To assess the impact of these treatments on cardiac health, mitochondrial function, and lifespan.
- To investigate the molecular mechanisms underlying treatment effects on cardiac pathology.
Main Methods:
- Utilized a conditional Fxnflox/null::MCK-Cre knockout (FXN-cKO) mouse model.
- Administered omaveloxolone and dimethyl fumarate (DMF) independently to FXN-cKO mice.
- Assessed cardiac function, gene expression (e.g., Nppb, Aldh1a3, Gdf15, Nqo1, HO-1, Sirt1, Atp2a, Mcu, Lgals3), oxidative stress, inflammation, hypertrophy, fibrosis, and survival.
Main Results:
- Omaveloxolone improved cardiac contractile function and reduced heart failure markers but did not prevent premature death, accelerating mortality in female mice.
- Both omaveloxolone and DMF restored SERCA2 and MCU expression and reduced CaMKIIδ phosphorylation, but only omaveloxolone improved cardiac function.
- Neither drug reduced cardiac hypertrophy, fibrosis, or rescued impaired mitochondrial function, and DMF did not improve cardiac function or survival.
Conclusions:
- Omaveloxolone enhances cardiac contractility in FA but fails to improve survival due to persistent cardiac fibrosis and wall stress.
- The accelerated mortality in female FXN-cKO mice treated with omaveloxolone requires further investigation.
- Current Nrf2 inducers show limited efficacy in addressing the complex pathology and lethality of FA cardiomyopathy.
