Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice

Ito, Kaori; Kimura, Shigemi; Ozasa, Shiro; Matsukura, Makoto; Ikezawa, Makoto; Yoshioka, Ken; Ueno, Hideto; Suzuki, Misao; Araki, Kimi; Yamamura, Ken Ichi; Miwa, Takeshi; Dickson, George; Thomas, Gail D.; Miike, Teruhisa

doi:10.1093/hmg/ddl151

Cited by 60 publications

(66 citation statements)

References 48 publications

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“…In the same time, we also demonstrated a 26% loss of a-SMA expression in young-adult mdx muscle (and >70% loss in old mdx), suggesting a decrease in perivascular SMCs, responsible for part of these deleterious effects. It has been demonstrated in vivo that the reexpression of dystrophin only in SMCs significantly ameliorates vasoregulation in mdx mice, 28 confirming the importance of perivascular cells (eg, smooth Q41 muscle) in blood flow regulation. One of the possible key factors is NO production alteration 29 or impairment of nNOS, 29e31 probably explaining the significant decrease in nNOS expression in both young-adult and old mdx mice, in our study.…”

Section: Early Loss Of Terminal Arterioles and Nnos Modifies Perfusiomentioning

confidence: 80%

Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice

Latroche

Matot

Martins-Bach

et al. 2015

The American Journal of Pathology

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Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease, caused by an absence of dystrophin, inevitably leading to death. Although muscle lesions are well characterized, blood vessel alterations that may have a major impact on muscle regeneration remain poorly understood. Our aim was to elucidate alterations of the vascular network organization, taking advantage of Flk1(GFP/+) crossed with mdx mice (model for human DMD where all blood vessels express green fluorescent protein) and functional repercussions using in vivo nuclear magnetic resonance, combining arterial spin-labeling imaging of perfusion, and (31)P-spectroscopy of phosphocreatine kinetics. For the first time, our study focused on old (12-month-old) mdx mice, displaying marked chronic muscle lesions, similar to the lesions observed in human DMD, in comparison to young-adult (3-month-old) mdx mice displaying only mild muscle lesions with no fibrosis. By using an original approach combining a specific animal model, state-of-the-art histology/morphometry techniques, and functional nuclear magnetic resonance, we demonstrated that the microvascular system is almost normal in young-adult in contrast to old mdx mice, displaying marked microvessel alterations, and the functional repercussions on muscle perfusion and bioenergetics after a hypoxic stress vary depending on stage of pathology. This original approach clarifies disease evolution and paves the way for setting up new diagnostic markers or therapeutic strategies.

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Section: Early Loss Of Terminal Arterioles and Nnos Modifies Perfusiomentioning

confidence: 80%

Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice

Latroche

Matot

Martins-Bach

et al. 2015

The American Journal of Pathology

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“…Third, the finding that PPMOE23 could also effectively enter and correct smooth muscle cells in the vasculature and the digestive system is striking and remains to be further investigated. It has been documented that dystrophin deficiency in blood vessel smooth muscles caused deficits in circulation and could be corrected after dystrophin restoration (35). Improvement of cardiac hemodynamic function and survival of PPMOE23-treated (two 30-mg/kg i.v.…”

Section: Discussionmentioning

confidence: 99%

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

Moulton

Iversen

et al. 2008

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

223

258

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Antisense oligonucleotide-mediated exon skipping is able to correct out-of-frame mutations in Duchenne muscular dystrophy and restore truncated yet functional dystrophins. However, its application is limited by low potency and inefficiency in systemic delivery, especially failure to restore dystrophin in heart. Here, we conjugate a phosphorodiamidate morpholino oligomer with a designed cellpenetrating peptide (PPMO) targeting a mutated dystrophin exon. Systemic delivery of the novel PPMO restores dystrophin to almost normal levels in the cardiac and skeletal muscles in dystrophic mdx mouse. This leads to increase in muscle strength and prevents cardiac pump failure induced by dobutamine stress in vivo. Muscle pathology and function continue to improve during the 12-week course of biweekly treatment, with significant reduction in levels of serum creatine kinase. The high degree of potency of the oligomer in targeting all muscles and the lack of detectable toxicity and immune response support the feasibility of testing the novel oligomer in treating Duchenne muscular dystrophy patients.M utations in the dystrophin gene underlie two forms of muscular dystrophy: Duchenne and Becker muscular dystrophy (DMD and BMD). DMD is caused mainly by nonsense and frame-shift mutations with little or no production of functional dystrophin protein, leading to disease onset in early childhood with lethal consequences. BMD is caused by mutations that typically create shortened but in-frame transcripts with production of partially functional dystrophin, leading to variable and often overt symptoms (1-3). Most DMD mutations occur within the rod domain, which spans more than half the length of the protein, but seems to have limited functional importance (4, 5). Antisense therapy uses specific oligomers to remove the mutated or additional exon(s) that disrupt the reading frame, thus restoring the expression of shortened forms of dystrophin protein retaining critical functions (6-11).We previously demonstrated that i.m. delivery of a specific 2Ј-O-methyl phosphorothioate antisense oligonucleotide (2ЈOMeAON) was able to skip targeted dystrophin exon 23 in mdx mouse, a model of DMD (9). This mouse carries a nonsense point mutation within exon 23 and lacks dystrophin expression (except in a few rare revertant fibers) in all muscles, including the heart (12, 13). Skipping the mutated exon 23 restored both the reading frame and dystrophin expression, with functional improvement of the treated muscles (14) [supporting information (SI) Fig. S1a]. Recently we showed that a phosphorodiamidate morpholino oligomer (PMO), E23ϩ7-18 targeting the junction of exon 23 and intron 23 of mouse dystrophin (referred to as PMOE23 hereafter), was able to induce up to functional levels of dystrophin expression in some skeletal muscles by regular i.v. injections in mdx mice (15). However, dystrophin expression induced by both 2ЈOMeAON and PMO required high doses and was highly variable between muscles and myofibers in terms of observed efficacy. Of greater conc...

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“…The parameters affected are cardiac pacemaker activity, myocardial contractility, and vasomotor tone [9]. Other causes that could be considered for altered BP readings in patients with muscular dystrophy are neurohumoral changes caused by inactivity of patients, abnormal baroreceptor-mediated reflexes originating from the diseased skeletal muscles and decreased fluid intake [6]. Despite a third of the visits being classified as having low BP, none of the patients reported symptoms like dizziness or syncope.…”

Section: Discussionmentioning

confidence: 99%

Under-recognition of Low Blood Pressure Readings in Patients with Duchenne Muscular Dystrophy

et al. 2015

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Duchenne muscular dystrophy (DMD), a recessive sex-linked hereditary disorder, is characterized by degeneration, atrophy, and weakness of skeletal and cardiac muscle. The purpose of this study was to document the prevalence of abnormally low resting BP recordings in patients with DMD in our outpatient clinic. The charts of 31 patients with DMD attending the cardiology clinic at Rush University Medical Center were retrospectively reviewed. Demographic data, systolic, diastolic, and mean blood pressures along with current medications, echocardiograms, and documented clinical appreciation and management of low blood pressure were recorded in the form of 104 outpatient clinical visits. Blood pressure (BP) was classified as low if the systolic and/or mean BP was less than the fifth percentile for height for patients aged ≤17 years (n = 23). For patients ≥18 years (n = 8), systolic blood pressure (SBP) <90 mmHg or a mean arterial pressure (MAP) <60 mmHg was recorded as a low reading. Patients with other forms of myopathy or unclear diagnosis were excluded. Statistical analysis was done using PASW version 18. BP was documented at 103 (99.01 %) outpatient encounters. Low systolic and mean BP were recorded in 35 (33.7 %) encounters. This represented low recordings for 19 (61.3 %) out of a total 31 patients with two or more successive low recordings for 12 (38.7 %) patients. Thirty-one low BP encounters were in patients <18 years old. Hispanic patients accounted for 74 (71.2 %) visits and had low BP recorded in 32 (43.2 %) instances. The patients were non-ambulant in 71 (68.3 %) encounters. Out of 35 encounters with low BP, 17 patients (48.6 %) were taking heart failure medication. In instances when patients had low BP, 22 (66.7 %) out of 33 echocardiography encounters had normal left ventricular ejection fraction. Clinician comments on low BP reading were present in 11 (10.6 %) encounters, and treatment modification occurred in only 1 (1 %) patient. Age in years (p = .031) and ethnicity (p = .035) were independent predictors of low BP using stepwise multiple regression analysis. Low BP was recorded in a significant number of patient encounters in patients with DMD. Age 17 years or less and Hispanic ethnicity were significant predictors associated with low BP readings in our DMD cohort. Concomitant heart failure therapy was not a statistically significant association. There is a need for enhanced awareness of low BP in DMD patients among primary care and specialty physicians. The etiology and clinical impact of these findings are unclear but may impact escalation of heart failure therapy.

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Smooth muscle-specific dystrophin expression improves aberrant vasoregulation in mdx mice

Cited by 60 publications

References 48 publications

Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice

Structural and Functional Alterations of Skeletal Muscle Microvasculature in Dystrophin-Deficient mdx Mice

Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer

Under-recognition of Low Blood Pressure Readings in Patients with Duchenne Muscular Dystrophy

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