Master of Science
Duchenne muscular dystrophy (DMD) is a progressive muscular and microvascular degenerative disease affecting 1 in 3,500 boys. Chronic inflammation in skeletal muscle causes the onset of fibrosis caused by impaired angiogenesis and myogenesis. Improving angiogenic outcomes is a high priority. Previous studies have shown treatment with exogenous angiopoietin-1 (ANG1), a vascular stabilizing factor, reduced inflammation, ischemia, and fibrosis in animal models of DMD. This study further characterized DMD disease progression and the effects of exogenous ANG1 treatment had on the skeletal microvascular niche in DMD mice. The inflammatory and angiogenic response in mdx/utrn+/- mouse gastrocnemius samples were evaluated with immunohistochemistry and RT-qPCR. The microvascular niche lacked key gene and protein expression at 8 and 10 weeks of age. This had a cascading effect resulting in reduced myofiber size. Two weeks after ANG1 treatment some key microvascular niche gene expression and proteins had increased which led to increased myofiber size.
Summary for Lay Audience
Duchenne muscular dystrophy (DMD) is a muscle wasting condition that begins early childhood. It affects about 1 in 3500 boys at birth. It begins between ages three and five with a weakening of the pelvic and shoulder muscles causing difficulty sitting, standing, and walking. The muscle loss worsens rapidly throughout their lives. By teenage years, patients with DMD become wheelchair dependent. Patients suffer from muscle loss, and low oxygen levels body-wide due to poor blood flow. The condition can be managed, and quality of life can be improved; however, there is no cure. Patients die young around age 30 due to heart failure. Modern therapies being developed to build muscles depend on healthy blood flow. Muscle blood vessels, where gases and nutrients are exchanged, in patients with DMD are leaky. These leaky blood vessels are what causes poor blood flow in the muscle. Oxygen levels decline, preventing the positive effects of any treatment. Angiopoietin-1 (ANG1) is a naturally occurring protein that prevents blood vessels from leaking and can improve blood flow in patients with DMD. Studies have shown ANG1 is too low in mouse models of DMD. This project further investigated and characterized changes of the muscle blood vessels in a mouse model of DMD, and changes to the muscle after treatment with ANG1. In the DMD mice, more blood vessels had grown, but production of key components tied to blood vessels had declined. New muscle was not able to grow properly and was partially replaced with connective tissue. Following ANG1 treatment, there were signs of healthy blood vessels and the production of key components being restored. Muscles grew too. This data suggests ANG1 treatment had a positive effect on blood vessels and muscles.
Efficacy of current therapies being developed are dependent upon the local muscle environment. Muscle capillaries, the blood vessels where gases and nutrients are exchanged between blood and organs, in patients with DMD are leaky. These leaky capillaries create worse conditions in the muscle environment as oxygen levels decline, stifling the efficacy of treatments. Angiopoietin-1 (ANG1) is a naturally occurring protein that prevents capillary from leaking and regulates their fitness. Studies showed ANG1 is depleted in mice models of DMD.
This project further investigated and characterized disease progression of the muscle environment in the mdx/utrn+/- mouse, a model of DMD, and changes to the muscle environment of DMD mice induced by ANG1 treatment.
In the DMD mice, more capillaries had grown, but production of key components tied to capillaries had declined. New muscle was being developed, but muscle fibers had still shrunk and been replaced with collagen. Following ANG1 treatment, there were signs of tightly sealed capillaries and the production of key components being restored. Muscle fibers grew too. This data suggests ANG1 treatment had a cascading effect on the muscle environment and shows its efficacy as a therapeutic for DMD that should be further researched.
McClennan, Andrew, "Characterization of the DMD mouse's dynamic skeletal muscle microvascular niche" (2023). Electronic Thesis and Dissertation Repository. 9124.
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