Vascular therapy for Duchenne muscular dystrophy (DMD)

Abstract

Duchenne muscular dystrophy (DMD) is a progressive disease characterized by the wasting of the muscles that eventually lead to difficulty moving and, ultimately, premature death from heart and respiratory complications. DMD deficiency is caused by mutations in the gene encoding dystrophin , which prevents skeletal muscle, cardiac muscle, and other cells from producing the functional protein. Located on the cytoplasmic face of the plasma membrane of muscle fibers, dystrophin serves as a component of the dystrophin glycoprotein complex (DGC), mechanically reinforces the sarcolemma, and stabilizes the DGC, preventing it from contraction-mediated muscle degradation. In DMD muscle, dystrophin deficiency leads to progressive fibrosis, myofiber damage, chronic inflammation, and dysfunction of the mitochondria and muscle stem cells. Currently, DMD is incurable, and treatment involves the administration of glucocorticoids in order to delay disease progression. In the presence of developmental delay, proximal weakness, and elevated serum creatine kinase levels, a definitive diagnosis can usually be made after an extensive review of the patient’s history and physical examination, as well as confirmation through muscle biopsy or genetic testing. Current standards of care include the use of corticosteroids to prolong ambulation and delay the onset of secondary complications, including respiratory muscle and cardiac functions. However, different studies have been carried out to show the relationship between vascular density and impaired angiogenesis in the pathogenesis of DMD. Several recent studies on DMD management are vascular targeted and focused on ischemia as a culprit for the pathogenesis of DMD. This review critically discusses approaches—such as modulation of nitric oxide (NO) or vascular endothelial growth factor (VEGF)-related pathways—to attenuate the dystrophic phenotype and enhance angiogenesis.

Microvascular Skeletal-Muscle Crosstalk in Health and Disease

“…DMD is characterized by the progressive wasting of muscles caused by a mutation in the gene encoding the myofiber protein, dystrophin [ 9 , 153 ]. As a component of the dystrophin–glycoprotein complex (DGC), dystrophin connects the basal lamina of the ECM to the inner actin-based cytoskeleton and thereby reinforces the sarcolemma and prevents contraction-mediated muscle degradation.…”

“…As a component of the dystrophin–glycoprotein complex (DGC), dystrophin connects the basal lamina of the ECM to the inner actin-based cytoskeleton and thereby reinforces the sarcolemma and prevents contraction-mediated muscle degradation. Accordingly, dystrophin deficiency leads to progressive myofiber damage and the replacement of muscle tissue by fibrotic or fibro-adipose tissue ([ 33 , 153 ] for review). Moreover, the myopathy of DMD is accompanied by a marked alteration in the morphology and function of mitochondria, including decreased oxidative phosphorylation, the enhanced generation of reactive oxygen species, and an opening of the MTP pore, effects leading to mitoptosis and myocyte apoptosis [ 154 , 155 ].…”

“…Indeed, in a dog model of DMD, animals exhibited a decrease in muscle capillary density and an increase in the distance between capillaries and muscle fibers [ 157 , 158 ]. Moreover, the MVU in the muscle of DMD patients showed marked structural alterations, and evidence suggested that DMD muscle is prone to impaired blood flow [ 9 , 153 , 159 ]. In a murine model of DMD, mice lacking dystrophin (mdx) exhibited decreased vascular density, and angiogenesis was markedly impaired in an mdx hindlimb-muscle ischemic mouse model [ 153 , 160 , 161 ].…”

“…Moreover, the MVU in the muscle of DMD patients showed marked structural alterations, and evidence suggested that DMD muscle is prone to impaired blood flow [ 9 , 153 , 159 ]. In a murine model of DMD, mice lacking dystrophin (mdx) exhibited decreased vascular density, and angiogenesis was markedly impaired in an mdx hindlimb-muscle ischemic mouse model [ 153 , 160 , 161 ]. Moreover, VEGF levels are significantly lower in mdx mice, and increasing VEGF expression by the administration of an adenovirus construct encoding VEGF or the transplantation of SCs expressing VEGF, improved vascularization as well as muscle regeneration [ 162 , 163 ].…”

“…A defect in the vasoconstrictor response induced by muscle-derived NO in DMD patients, particularly during exercise, results in functional muscle ischemia. Accordingly, vascular dysfunction has been suggested as an underlying pathogenic mechanism of muscle injury in DMD and a target for the treatment of DMD patients ([ 9 , 153 ] for review).…”