A Nitrate Ester of Sedative Alkyl Alcohol Improves Muscle Function and Structure in a Murine Model of Duchenne Muscular Dystrophy

Abstract

Nitric oxide (NO) has major physiological and cellular effects on muscle growth, repair, and function. In most muscle biopsies from humans with myopathies, sarcolemma-localized neuronal nitric oxide synthase (nNOS) is either reduced or not detected, particularly in dystrophin-deficient Duchenne muscular dystrophy (DMD). Abnormal NO signaling at the sarcolemmal level is integrally involved in the pathogenesis and accounts, at least in part, for the muscle weakness of DMD. Dystrophic muscle fibers exhibit an increased susceptibility to contraction-induced membrane damage. Muscle relaxants function to prevent muscle wasting by decreasing nerve impulses and reducing calcium influx that regulates tensing or tightening of muscle fibers. We have recently developed a new class of nitric esters that combines the pharmacological functions of NO and muscle relaxation. Here, we report the synthesis and properties of the nitric ester (MMPN) of 2-methyl-2-n-propyl-1,3-propanediol (MPP) and its effect in mdx dystrophic mice, a murine model of DMD. MMPN produced significant improvements in biochemical, pathological, and functional phenotypes in the mouse model. The endurance of exercise was extended by 47% in time to exhaustion and 84% in running distance. Serum CK level was decreased by 30%. Additionally, MMPN decreased intracellular free calcium concentration without causing skeletal muscle weakness. No hepatic or renal toxicities were observed during the study. Our investigations unveil a potential new treatment for muscular diseases.

Physical exercise associated with NO production: signaling pathways and significance in health and disease

“…Abnormal NO-signaling occurs in degenerative muscle diseases including muscular atrophies and dystrophies (Wang and Lu, 2013 ).…”

Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy

“…Indeed, 6 months delivery of a nitric ester derivative of sedative alkyl alcohol (administered at 40 mg/kg 5 days/week) has been shown to enhance the vascular density of skeletal muscle, as well as exercise performance and strength in mdx mice, with a marked decrease in the free intracellular Ca 2+ concentration of skeletal muscle [74]. In addition, the NO-donating nitric ester increased muscle fibre size while concomitantly reducing the population of regenerating fibres, suggestive of decreased damage [74].…”

“…In addition, the NO-donating nitric ester increased muscle fibre size while concomitantly reducing the population of regenerating fibres, suggestive of decreased damage [74]. Similarly, 7 months of 30 mg/kg naproxcinod, a non-steroidal anti-inflammatory drug (NSAID) with NO-donating properties, in food, had a beneficial effect on the running capacity of mdx mice with both time to exhaustion and whole body strength improved [75].…”

Electrochemical Determination of Ca2+ Based On Recycling Formation of Highly Selective DNAzyme and Gold Nanoparticle-Mediated Amplification

“…Calcium is one of the most essential elements in the human body . It not only comprises 1–2% of body weight, but also participates in metabolism and mineral homeostasis. , Ionized calcium (Ca 2+ ) levels in certain biofluids have been demonstrated to modulate numerous physiological and pathological processes, affecting different functions of organs or systems, such as neural signaling, biomineralization, acid–base balance, and muscle action. − Excessive alternation of Ca 2+ may lead to diverse disorders including hyperparathyroidism, osteoporosis, renal disorder, and muscle tightening. − The level of Ca 2+ can even be used for clinical estimation . Thus, it is necessary to develop reliable and sensitive methods for the detection of Ca 2+ .…”