Effect of sildenafil on skeletal and cardiac muscle in <scp>B</scp>ecker muscular dystrophy

Witting, Nanna; Kruuse, Christina; Nyhuus, Bo; Prahm, Kira Philipsen; Citirak, Gülsenay; Lundgaard, Stine J.; Huth, Sebastian von; Vejlstrup, Niels; Lindberg, Ulrich; Krag, Thomas; Vissing, John

doi:10.1002/ana.24216

Cited by 42 publications

(48 citation statements)

References 26 publications

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“…Such studies have yielded mixed results in animal models, with modest improvements in cardiac function and pathology. Furthermore, human trials have offered little evidence of a beneficial cardiac effect of sildenafil treatment in adults with DMD or Becker muscular dystrophy (58,59). In light of our findings, it is possible that the shortcomings of these previous studies reflect the existence of other functional targets of muscle-derived NO, or additional targets of altered AMPK regulation, that contribute to dysfunction in dystrophic muscle (43,60,61).…”

Section: Discussionmentioning

confidence: 64%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin-deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle.T he muscular dystrophies are a group of muscle wasting disorders characterized by progressive weakening and degeneration of striated muscle. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder caused by genetic disruption of dystrophin (1) that affects 1 in 3,500-5,000 males (2, 3). DMD and several other types of muscular dystrophy result from disruption of the dystrophin-glycoprotein complex (DGC), a structure that spans the sarcolemma and forms a mechanical linkage between the cytoskeleton and the extracellular matrix via the association of dystrophin with subsarcolemmal γ-actin and the binding of α-dystroglycan to laminin (4). The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1, 5-7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8, 9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).In addition to this structural role, a signaling function for the DGC has been proposed based on its association with several signaling proteins including Grb2-Sos1 (15), MEK and ERK (16), heterotrimeric G protein subunits (17, 18), archvillin (19), and neuronal nitric oxide synthase (n...

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Section: Discussionmentioning

confidence: 64%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In animal studies sildenafil is reported to pass the blood-brain barrier [51], though similar is not clearly evident in humans [52]. Muscle biopsies from the patients showed reduced nNOS protein expression and a corresponding reduction in PDE5 expression [23], which could cause the patients to be less sensitive to PDE5 inhibitors.…”

Section: Discussionmentioning

confidence: 93%

“…The reported reduced recruitment of sufficient blood flow in patients with BMD during muscle activity responsible for relative ischemia [37] is improved by PDE5 inhibition in some studies [22,38,39], but not in all of them [23,24], which may relate to variations in methods applied. Corresponding reduced brain blood flow recruitment during activation was hypothesized to be present in patients with BMD and restored by PDE5 inhibition; the current data partly support this hypothesis.…”

Section: Discussionmentioning

confidence: 98%

“…Only 17 patients fulfilled the inclusion criteria and agreed to participate [23], and just 12 completed all scans on all 3 scanning days. Owing to the low number of eligible patients, a crossover design was chosen to improve the power.…”

Section: Discussionmentioning

confidence: 99%

“…Sildenafil is used to treat erectile dysfunction and pulmonary hypertension, and works by augmenting endogenous cGMP levels, thus promoting a normal NO response. Recently sildenafil/PDE5 administration was shown to reduce skeletal muscle and cardiac dysfunction and to ameliorate dystrophy in a mouse model of DMD [20][21][22], although no positive effect was found on skeletal or cardiac muscle function and brachial arterial forearm flow in 17 patients with BMD [23] or 15 patients with BMD/DMD [24]. In healthy subjects, including males and females, sildenafil does not change the cerebral blood flow (CBF) after a single oral dose of 100 mg measured by single photon emission computer tomography and transcranial Doppler [25], but it may do so in patients with dysfunctional NO signaling [26], such as patients with BMD.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

et al. 2017

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Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment.Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

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Muscular dystrophy patients show low exercise‐induced blood flow in muscles with normal strength

Gera,

Shavit‐Stein,

Amichai

et al. 2024

Ann Clin Transl Neurol

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ObjectiveNeuromuscular evaluation increasingly employs muscle ultrasonography to determine muscle thickness, mean grayscale echointensity, and visual semiquantitative echotexture attenuation. However, these measures provide low sensitivity for detection of mild muscle abnormality. Exercise‐induced intramuscular blood flow is a physiologic phenomenon, which may be impaired in mildly affected muscles, particularly in dystrophinopathies, and may indicate functional muscle ischemia. We aimed to determine if muscle blood flow is reduced in patients with neuromuscular disorders and preserved muscle strength, and if it correlates with echointensity and digital echotexture measurements.MethodsPeak exercise‐induced blood flow, echointensity, and echotexture were quantified in the elbow flexor muscles of 15 adult patients with Becker muscular dystrophy (BMD) and 13 patients with other muscular dystrophies (OMD). These were compared to 17 patients with Charcot–Marie–Tooth type 1 (CMT1) neuropathy and 21 healthy adults from a previous study.ResultsMuscle blood flow was reduced in all patient groups compared to controls, most prominently in BMD patients (p < 0.0001). Echointensity was similarly increased in all patient groups (p < 0.05), while echotexture was reduced only in muscular dystrophy patients (p ≤ 0.002). In BMD, blood flow correlated with echotexture (Pearson r = 0.6098, p = 0.0158) and strength (Spearman r = 0.5471; p = 0.0370). In patients with normal muscle strength, reduced muscle blood flow was evident in all patient groups (p < 0.001), echotexture was reduced in BMD and OMD (p < 0.01), and echointensity was increased in CMT (p < 0.05).InterpretationMuscle blood flow is a sensitive measure to detect abnormality, even in muscles with normal strength. Increased echointensity may indicate a neurogenic disorder when strength is preserved, while low echotexture suggests a dystrophic disease.

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Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy

Cited by 42 publications

References 26 publications

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

Muscular dystrophy patients show low exercise‐induced blood flow in muscles with normal strength

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