Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and the development of a dilated cardiomyopathy (DCM), which is the leading cause of death in DMD patients. Despite knowing the cause of DMD, there are currently no therapies which can prevent or reverse its inevitable progression. We have used whole body periodic acceleration (WBPA) as a novel tool to enhance intracellular constitutive nitric oxide (NO) production. WBPA adds small pulses to the circulation to increase pulsatile shear stress, thereby upregulating endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) and subsequently elevating the production of NO. Myocardial cells from dystrophin-deficient 15-month old mdx mice have contractile deficiency, which is associated with elevated concentrations of diastolic Ca2+ ([Ca2+]d), Na+ ([Na+]d), and reactive oxygen species (ROS), increased cell injury, and decreased cell viability. Treating 12-month old mdx mice with WBPA for 3 months reduced cardiomyocyte [Ca2+]d and [Na+]d overload, decreased ROS production, and upregulated expression of the protein utrophin resulting in increased cell viability, reduced cardiomyocyte damage, and improved contractile function compared to untreated mdx mice.
Highlights
Duchenne muscular dystrophy (DMD) is caused by the lack of expression of dystrophin, which forms part of the dystroglycan structural complex in the sarcolemma (Hoffman et al, 1987; Muntoni et al, 2003)
These results demonstrate that whole body periodic acceleration (WBPA) treatment reduced cardiomyocytes Ca2+ and Na+ overload found in 15-month WT and mdx mice
Our results demonstrate that WBPA treatment provides cardioprotection and improves myocyte function in dystrophindeficient mdx mice with established cardiomyopathy by reducing intracellular Ca2+ and Na+ overload, reducing intracellular reactive oxygen species (ROS) generation, enhancing the expression of utrophin, reducing cardiomyocyte damage, with the end result of improvement of cell viability and contractile function
Summary
Duchenne muscular dystrophy (DMD) is caused by the lack of expression of dystrophin, which forms part of the dystroglycan structural complex in the sarcolemma (Hoffman et al, 1987; Muntoni et al, 2003). A disturbed intracellular Ca2+ regulation has been found in smooth muscle (Lopez et al, 2020) and neurons (Lopez et al, 2016) from dystrophic mice. In addition to their progressive debilitating skeletal muscle myopathy, DMD patients as they aged develop a lethal dilated cardiomyopathy (DCM) with arrhythmias, myocardial fibrosis, and congestive heart failure. Corticosteroid therapy still represents the primary treatment option, but it has serious side effects, limited skeletal muscle improvement, and it has and few to no benefits in preventing or treating DMD cardiomyopathy (Malik et al, 2012; Bylo et al, 2020)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
