Publications by authors named "Zachary M Howard"

3 Publications

  • Page 1 of 1

Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model.

JCI Insight 2021 Apr 8;6(7). Epub 2021 Apr 8.

Department of Physiology & Cell Biology and Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.
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http://dx.doi.org/10.1172/jci.insight.146511DOI Listing
April 2021

Early Inflammation in Muscular Dystrophy Differs between Limb and Respiratory Muscles and Increases with Dystrophic Severity.

Am J Pathol 2021 04 23;191(4):730-747. Epub 2021 Jan 23.

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio; Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio. Electronic address:

Duchenne muscular dystrophy (DMD) is a genetic, degenerative, striated muscle disease exacerbated by chronic inflammation. Mdx mice in the genotypic DMD model poorly represent immune-mediated pathology observed in patients. Improved understanding of innate immunity in dystrophic muscles is required to develop specific anti-inflammatory treatments. Here, inflammation in mdx mice and the more fibrotic utrn;mdx Het model was comprehensively investigated. Unbiased analysis showed that mdx and Het mice contain increased levels of numerous chemokines and cytokines, with further increased in Het mice. Chemokine and chemokine receptor gene expression levels were dramatically increased in 4-week-old dystrophic quadriceps muscles, and to a lesser extent in diaphragm during the early injury phase, and had a small but consistent increase at 8 and 20 weeks. An optimized direct immune cell isolation method prevented loss of up to 90% of macrophages with density-dependent centrifugation previously used for mdx flow cytometry. Het quadriceps contain higher proportions of neutrophils and infiltrating monocytes than mdx, and higher percentages of F4/80, but lower percentages of F4/80 cells and patrolling monocytes compared with Het diaphragms. These differences may restrict regenerative potential of dystrophic diaphragms, increasing pathologic severity. Fibrotic and inflammatory gene expression levels are higher in myeloid cells isolated from Het compared with mdx quadriceps, supporting Het mice may represent an improved model for testing therapeutic manipulation of inflammation in DMD.
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http://dx.doi.org/10.1016/j.ajpath.2021.01.008DOI Listing
April 2021

Mineralocorticoid Receptor Signaling Contributes to Normal Muscle Repair After Acute Injury.

Front Physiol 2019 25;10:1324. Epub 2019 Oct 25.

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States.

Acute skeletal muscle injury is followed by a temporal response of immune cells, fibroblasts, and muscle progenitor cells within the muscle microenvironment to restore function. These same cell types are repeatedly activated in muscular dystrophy from chronic muscle injury, but eventually, the regenerative portion of the cycle is disrupted and fibrosis replaces degenerated muscle fibers. Mineralocorticoid receptor (MR) antagonist drugs have been demonstrated to increase skeletal muscle function, decrease fibrosis, and directly improve membrane integrity in muscular dystrophy mice, and therefore are being tested clinically. Conditional knockout of MR from muscle fibers in muscular dystrophy mice also improves skeletal muscle function and decreases fibrosis. The mechanism of efficacy likely results from blocking MR signaling by its endogenous agonist aldosterone, being produced at high local levels in regions of muscle damage by infiltrating myeloid cells. Since chronic and acute injuries share the same cellular processes to regenerate muscle, and MR antagonists are clinically used for a wide variety of conditions, it is crucial to define the role of MR signaling in normal muscle repair after injury. In this study, we performed acute injuries using barium chloride injections into muscles both in myofiber MR conditional knockout mice on a wild-type background (MRcko) and in MR antagonist-treated wild-type mice. Steps of the muscle regeneration response were analyzed at 1, 4, 7, or 14 days after injury. Presence of the aldosterone synthase enzyme was also assessed during the injury repair process. We show for the first time aldosterone synthase localization in infiltrating immune cells of normal skeletal muscle after acute injury. MRcko mice had an increased muscle area infiltrated by aldosterone synthase positive myeloid cells compared to control injured animals. Both MRcko and MR antagonist treatment stabilized damaged myofibers and increased collagen infiltration or compaction at 4 days post-injury. MR antagonist treatment also led to reduced myofiber size at 7 and 14 days post-injury. These data support that MR signaling contributes to the normal muscle repair process following acute injury. MR antagonist treatment delays muscle fiber growth, so temporary discontinuation of these drugs after a severe muscle injury could be considered.
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http://dx.doi.org/10.3389/fphys.2019.01324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830343PMC
October 2019