Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is the most frequent and severe form of muscular dystrophy. The disease presents with progressive body-wide muscle deterioration and, with recent advances in respiratory care, cardiac involvement is an important cause of morbidity and mortality. DMD is caused by mutations in the dystrophin gene resulting in the absence of dystrophin and, consequently, disturbance of other proteins that form the dystrophin-associated protein complex (DAPC), including neuronal nitric oxide synthase (nNOS). The molecular mechanisms that link the absence of dystrophin with the alteration of cardiac function remain poorly understood but disruption of NO-cGMP signalling, mishandling of calcium and mitochondrial disturbances have been hypothesized to play a role. cGMP and cAMP are second messengers that are key in the regulation of cardiac myocyte function and disruption of cyclic nucleotide signalling leads to cardiomyopathy. cGMP and cAMP signals are compartmentalised and local regulation relies on the activity of phosphodiesterases (PDEs). Here, using genetically encoded FRET reporters targeted to distinct subcellular compartments of neonatal cardiac myocytes from the DMD mouse model mdx, we investigate whether lack of dystrophin disrupts local cyclic nucleotide signalling, thus potentially providing an early trigger for the development of cardiomyopathy. Our data show a significant alteration of both basal and stimulated cyclic nucleotide levels in all compartments investigated, as well as a complex reorganization of local PDE activities.

Tuning the Consonance of Microscopic Neuro-Cardiac Interactions Allows the Heart Beats to Play Countless Genres

“…Altogether, this data supports the dystroglycan complex, as a component of the NCJ, might have a role in the functional “SN-CM” communication. Interestingly, it has recently been demonstrated that lack of dystrophin, by affecting the subplasmalemmal cytoskeletal organization, leads to disarray of cAMP compartments, reflecting on the efficiency of β-AR stimulation ( Brescia et al, 2020 ). While this was observed in cultured CMs, together with our observations, these results prompt the idea that absence of dystrophin may lead to profound alteration in the local nature of β-AR activators (neurons) and signaling, thus reflecting on neuro-cardiac fidelity.…”

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

“…Dystrophin deficiency leads to down-regulated expression and mislocalization of the source of nitric oxide (NO) in skeletal muscle ( Brescia et al, 2020 ). NO is used to stimulate the production of cyclic guanosine monophosphate (cGMP), and the NO-cGMP signaling pathway is required to balance muscle oxygenation and prevent excessive vasoconstriction caused by exercising ( Percival et al, 2011 ).…”

“…NO is used to stimulate the production of cyclic guanosine monophosphate (cGMP), and the NO-cGMP signaling pathway is required to balance muscle oxygenation and prevent excessive vasoconstriction caused by exercising ( Percival et al, 2011 ). In mdx mice, the suppression of the NO-cGMP signaling pathway promotes skeletal muscle weakness, vascular dysfunction and defective exercise performance ( Asai et al, 2007 ; Garbincius and Michele, 2015 ; Hörster et al, 2015 ; Brescia et al, 2020 ). The inhibitors of phosphodiesterase 5 (PDE5) can suppress cGMP breakdown and further amplify the signal of NO-cGMP pathways ( Dombernowsky et al, 2018 ).…”

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

“…Cardiomyocyte death in DMD patients is associated with the absence of dystrophin-related mechanical functions and signaling. As in skeletal muscle, cardiomyocytes struggle with an overload of Ca 2+ , the absence of nNOS/ NO signaling [217][218][219] and the overproduction of ROS, which lead to the progression of pathological alterations. Law et al [220] summarized known mechanisms responsible for mishandling Ca 2+ in dilating cardiomyopathy in DMD hearts and reported experimental therapeutic targets that could address this issue.…”