Browsing by Subject "Skeletal muscle"
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Item Cross-talk between the skeletal muscle stem cells and endothelial cells(2018-03) Verma, MayankDuchenne muscular dystrophy (DMD) is a progressive neurodegenerative muscle disease caused by the absence of the dystrophin protein. While the muscle develops normally, it is susceptible to contraction-induced damage resulting in segmental necrosis. The damaged muscle is repaired by the resident stem cell, the satellite cell. However, after continuous rounds of regeneration/degeneration, the satellite cell pool is exhausted and the muscle fiber is replaced with fatty infiltrate and fibrosis. Although dystrophin is commonly studied in the muscle cells, its role in the vasculature has only recently been appreciated. The overall goal of research conducted in this thesis is to elucidate the role of the vascular endothelial cell, satellite cell, and their interactions in normal and DMD muscle. We have previously shown that when performed in developmental, there was increased angiogenesis and capillary density in mdx mice with the deletion of one allele for the Vascular Endothelial Growth Factor (VEGF) receptor, Flt1 gene. Interestingly, this led to an increase in muscle stem cells (satellite cells) and improved histological and contractile function. These data suggest that increasing the vasculature can increase the satellite cell pool and ameliorate the dystrophic phenotype seen in DMD model mice. However, the mechanism behind this interaction remains unclear. This thesis will attempt to fill in this gap in knowledge. In the following chapters (Figure 1), we identified VEGF receptors expressed on satellite cells and show that VEGFA binds to FLT1 to protect the cells from apoptosis. We investigated the cell-cell crosstalk between satellite cells and endothelial cells using 3-dimentional imaging. We showed that satellite cells secrete VEGFA to pattern the capillaries and in turn the endothelial cells keep the satellite cells in a quiescent state through expression of the notch ligand Delta-like protein 4 (DLL4). From a disease context, we utilized conditional Flt1 knockout mice to examine whether post-natal abolishment of Flt1 results in increased capillary density in the skeletal muscle and an improvement in the dystrophic phenotype in the mdx mice. Lastly, we utilized several strategies for recapitulating this phenomenon in a therapeutic manner. This will serve as a proof of concept to see whether FLT1 can be used as a drug target for the treatment of DMD. This information has applications beyond DMD as VEGF and its receptors are also under investigation for the treatment of peripheral artery disease, ischemic injury, as well as anti-cancer therapy. Outcomes from these studies will not only broaden our understanding of the juxtavascular niche for satellite cells but will also lead to the development of angiogenesis-targeted treatment options for DMD.Item Modulating Physical Activity to Enhance Rehabilitative Outcomes(2022-05) Basten, AlecSkeletal muscle is the primary organ for human movement. In this way, muscle is highly organized by architecture, fiber type, excitation-contraction coupling, and metabolism to supply energy, contract, and transmit force. When any of these aspects is disrupted, for example resulting from injury, there can be decreased force production capacity and impaired movement. Skeletal muscle is remarkable in its ability to repair, regenerate and adapt. Therefore, most injuries are recoverable. Though, in severe cases of muscle injury (i.e., volumetric muscle loss injury; VML), there is a permanent loss of function. For recoverable muscle injuries, rehabilitation improves recovery. However, rehabilitation remains minimally effective for VML injury and lacks physiologic rationale as to why. Preclinical models for rehabilitation of VML are limited and must expand to test a broader scope of rehabilitation variables (i.e., timing, type, intensity, and duration). One variable that may impact the response to rehabilitation is physical activity. Currently, extreme methods of activity restriction (i.e., hindlimb unloading, immobilization, and denervation) dominate activity restriction studies. Chapter one of this thesis is a review of the literature relating to skeletal muscle, skeletal muscle injury, physical rehabilitation, VML injury, and physical activity. The second chapter of this thesis evaluates a combined electrical stimulation and range of motion as a rehabilitation approach, and an underutilized model of restricting activity that limits housing space instead of completely unloading skeletal muscle. Collectively the data indicate that this rehabilitation impaired muscle function. Restricting activity recovered some impairment, suggesting restricted activity might improve response to rehabilitation. However, restricting activity also resulted in whole body metabolic impairment, a side effect that should be seriously considered if restricting activity is to be used as an adjuvant to enhance rehabilitation. Finally, chapter three dives into conclusions and future directions of this work. Future studies should be aimed at expanding the repertoire of rehabilitation models used for the rehabilitation of VML injury and explore other variables, particularly when to commence rehabilitation, what mode of rehabilitation might be best and most translatable, and how restricting activity may play a role.Item Physical activity and muscle function in females: Impact of ovarian hormones, bazedoxifene, and estrogen receptor alpha(2018-12) Cabelka, ChristineOverall, my dissertation work had three main objectives: 1) critically evaluate the literature to determine if hormone therapy increases physical activity in postmenopausal women, 2) determine the effects of estradiol and progesterone on physical activity and skeletal muscle function in female mice, and 3) determine the effects of bazedoxifene on the musculoskeletal system. First, I performed a systematic review and meta-analysis (Chapter 3), which determined that there is a lack of evidence to conclude that hormone therapy does not affect physical activity in postmenopausal women. Although there is not a clear link between ovarian hormones and physical activity in women, there is a clear link in rodent models. I then identified that a combined treatment of estradiol+progesterone after ovariectomy increased physical activity in the form of wheel running distance and blunted susceptibility to fatigue in the soleus muscles of female mice (Chapter 4). Additionally, I determined that estrogen receptor is likely the predominant receptor through which estradiol functions to elicit its effects on skeletal muscle fatigue (Chapter 4). Finally, due to declines in the clinical use of estrogen-based hormone therapy in postmenopausal women, I investigated the effects of bazedoxifene, a selective estrogen receptor modulator, on the musculoskeletal system. This investigation showed that bazedoxifene has tissue selective effects on adipose tissue, skeletal muscle, and bone (Chapter 5). The work contained in my dissertation highlights a number of hormones or hormone analogues that impact physical activity, as well as identifies estrogen receptor as a mechanism through which these compounds elicit their effects on skeletal muscle.