Prevention and Treatment of Duchenne Cardiomyopathy with Hydrogen Sulfide‐Donor Therapy

Abstract

BackgroundDuchenne muscular dystrophy (DMD) is the most frequently inherited human myopathy and represents the most devastating type of muscular dystrophy. This progressive disease is caused by X‐linked recessive defects in the gene encoding for the structural protein, dystrophin. Young boys with DMD exhibit symptoms between 3–5 years of age, primarily involving skeletal muscles. Although the heart is also impacted, limited exercise tolerance masks early symptoms of cardiomyopathy (DMD‐CM). The defects in dystrophin in cardiac tissue lead to loss of membrane integrity, extracellular calcium influx and subsequent cardiomyocyte necrosis, inflammation and increased overall fibrosis. Respiratory failure has long been the leading cause of death in boys with DMD, however, with the advent of respiratory therapy, patients with DMD may now survive longer to unfortunately die in the 2nd or 3rd decade of life from heart failure. Based on its mito‐protective, anti‐inflammatory, anti‐apoptotic and anti‐fibrotic effects, we believe that hydrogen sulfide (H2S) is a promising candidate for therapy against the devastating consequences of DMD‐CM.Methods‘Humanized’ dystrophic G2 mice (shorter telomeres) were generated by inbreeding G1 mdx4cv/mTR mice. The effects of SG1002, an orally active slow releasing H2S prodrug, were tested in the G2 mice (40 mg/kg) either immediately after weaning (~3 weeks of age; Early Treatment) or after cardiac dysfunction (~7 months of age; Late Treatment). Cardiac function was analyzed by echocardiography. Muscle fibrosis was assessed via picrosirius red staining of diaphragm, gastrocnemius, and heart collected at 2, 4 and 9 months. Cardiac mitochondria and protein were isolated to measure oxidative phosphorylation and NLRP3 expression, respectively.ResultsEarly treatment with SG1002 preserved cardiac function (ejection fraction; EF) throughout study duration, whereas untreated mice exhibited significant decline in EF by 4 months of age and continued to worsen over time (Fig. A). Delayed treatment with SG1002 significantly improved EF within 1 month after treatment initiation. SG1002 also significantly attenuated fibrosis in the diaphragm and gastrocnemius, and had a tendency to decrease cardiac fibrosis by 9 months of age (Fig. B). A steady decline in mitochondrial function was observed over time in untreated mice compared to wild type mice (−26%), which was attenuated with SG1002 (−12%, P<0.05 vs. untreated group). Although there was no difference in NLRP3 expression in the heart of G2 mice at 4 months of age compared to wild type, a significant 2‐fold increase in cardiac NLRP3 expression was observed by 9 months (Fig. C).ConclusionIn a ‘humanized’ mouse model of DMD, our results strongly support daily H2S therapy for preservation of cardiac function, attenuation of skeletal muscle fibrosis and cardiac NLRP3 expression. Accordingly, modulation of the inflammasome and scar formation with H2S may represent an important mechanism to mitigate DMD‐CM as well as skeletal muscle injury.Support or Funding InformationR01HL133167 to FNSThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hydrogen sulfide as a therapeutic option for the treatment of Duchenne muscular dystrophy and other muscle-related diseases

“…The initial study focused on evaluating the cardioprotective potential of H 2 S. A brief scientific report (published in the form of the conference abstract) by Cain et al [ 257 ] shows that supplementation of ‘humanized’ dystrophic mice ( mdx 4cv /mTR G2 mouse model with ‘humanized’ telomere lengths) with an orally active slow-release H 2 S prodrug (SG1002) results in maintenance of the ejection fraction (ET) at a level similar to wild-type mice, indicating preserved cardiac function. Furthermore, a decreasing trend in cardiac fibrosis was observed in the treated animals versus the untreated group.…”

“…In addition to cardioprotective effects, Cain et al found attenuated fibrosis in the gastrocnemius and diaphragm after SG1002 treatment [ 257 ]. More studies demonstrating the beneficial muscle-related effects of H 2 S in mitigating the progression of DMD were published in 2021.…”

“…A summary of basic information on various H 2 S donors is provided in Table 1. However, we encourage the readers to seek more details in other articles that focus on donor, orally active [160,257,279] donor chemistry, their pros and cons, and possible applications [140,162,163].…”