Dataset Information

RAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

ABSTRACT: Dilated cardiomyopathy is a common cause of death in patients with Duchenne muscular dystrophy (DMD). Gene therapies for DMD must, therefore, have a therapeutic impact in cardiac as well as skeletal muscles. Our previous studies have shown that GALGT2 overexpression in mdx skeletal muscles can prevent muscle damage. Here we have tested whether rAAVrh74.MCK.GALGT2 gene therapy in mdx cardiac muscle can prevent the loss of heart function. Treatment of mdx hearts with rAAVrh74.MCK.GALGT2 1 day after birth did not negatively alter hemodynamic function, tested at 3 months of age, and it prevented early left ventricular remodeling and expression of fibrotic gene markers. Intravenous treatment of mdx mice with rAAVrh74.MCK.GALGT2 at 2 months of age significantly improved stroke volume and cardiac output compared to mock-treated mice analyzed at 17 months, both at rest and after stimulation with dobutamine. rAAVrh74.MCK.GALGT2 treatment of mdx heart correlated with increased glycosylation of ?-dystroglycan with the CT glycan and increased utrophin protein expression. These data provide the first demonstration that GALGT2 overexpression can inhibit the loss of cardiac function in the dystrophin-deficient heart and, thus, may benefit both cardiac and skeletal muscles in DMD patients.

SUBMITTER: Xu R

PROVIDER: S-EPMC6403484 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

Xu Rui R Jia Ying Y Zygmunt Deborah A DA Martin Paul T PT

Molecular therapy : the journal of the American Society of Gene Therapy 20190115 3

Dilated cardiomyopathy is a common cause of death in patients with Duchenne muscular dystrophy (DMD). Gene therapies for DMD must, therefore, have a therapeutic impact in cardiac as well as skeletal muscles. Our previous studies have shown that GALGT2 overexpression in mdx skeletal muscles can prevent muscle damage. Here we have tested whether rAAVrh74.MCK.GALGT2 gene therapy in mdx cardiac muscle can prevent the loss of heart function. Treatment of mdx hearts with rAAVrh74.MCK.GALGT2 1 day afte ...[more]

PMID: 30711447

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Project description:Functional magnetic resonance imaging (fMRI) has been used to infer age-differences in neural activity from the hemodynamic response function (HRF) that characterizes the blood-oxygen-level-dependent (BOLD) signal over time. BOLD literature in healthy aging lacks consensus in age-related HRF changes, the nature of those changes, and their implications for measurement of age differences in brain function. Between-study discrepancies could be due to small sample sizes, analysis techniques, and/or physiologic mechanisms. We hypothesize that, with large sample sizes and minimal analysis assumptions, age-related changes in HRF parameters could reflect alterations in one or more components of the neural-vascular coupling system. To assess HRF changes in healthy aging, we analyzed the large population-derived dataset from the Cambridge Center for Aging and Neuroscience (CamCAN) study (Shafto et al., 2014). During scanning, 74 younger (18-30 years of age) and 173 older participants (54-74 years of age) viewed two checkerboards to the left and right of a central fixation point, simultaneously heard a binaural tone, and responded via right index finger button-press. To assess differences in the shape of the HRF between younger and older groups, HRFs were estimated using FMRIB's Linear Optimal Basis Sets (FLOBS) to minimize a priori shape assumptions. Group mean HRFs were different between younger and older groups in auditory, visual, and motor cortices. Specifically, we observed increased time-to-peak and decreased peak amplitude in older compared to younger adults in auditory, visual, and motor cortices. Changes in the shape and timing of the HRF in healthy aging, in the absence of performance differences, support our hypothesis of age-related changes in the neural-vascular coupling system beyond neural activity alone. More precise interpretations of HRF age-differences can be formulated once these physiologic factors are disentangled and measured separately.

Dataset Information

RAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

Publications

rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart.

Similar Datasets

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