Semester

Summer

Date of Graduation

2013

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

I. Mark Olfert.

Abstract

Our objective was to elucidate the effects of TSP-1 on skeletal muscle structure and function, and its potential role in the progression of skeletal muscle dysfunction. The central hypothesis was that TSP-1 is a critical negative regulator of skeletal muscle angiogenesis. In chapter 3, we used a TSP-1 mimetic delivered by mini osmotic pumps to show that TSP-1 can reduce capillarity across three distinct muscle types. We found that those given the mimetic had a 35% decrease in soleus capillarity, a 20% decrease in the gastrocnemius, and an 11% decrease in the plantaris. This confirmed the critical role that TSP-1 plays in physiological skeletal muscle angiogenesis. Despite previous evidence showing that TSP-1 is an important regulator of apoptosis in tumorigenesis, we found no apoptosis in the skeletal muscle of those animals treated with the TSP-1 mimetic, as measured by TUNEL staining or cell death ELISA. Further, again using this same mimetic, in chapters 3 and 4 we failed to find any change in whole body exercise, as measured by maximal running speed, or direct muscle function as measured by ex vivo muscle simulation, in relation to the TSP-1 induced capillary rarefaction. This may further support the notion that it is not simply one factor that controls exercise capacity, but a combination of many different components and systems. Further, previous evidence suggested that a TSP-1/TNFa axis could be controlling skeletal muscle capillarity rarefaction in chronic systemic inflammation. In chapter 5 we examined the role overexpression of TNFa has on skeletal muscle capillary regression in a mouse model of chronic lung disease. Despite showing a 16% decrease in capillarity of the soleus, we found no change in TSP-1 expression. What factors are at play in this specific disease model remains unknown; however our data suggests that TSP-2 could be central to pathological capillary regression seen with this model. Finally, in chapter 4 we also suggest that TSP-1 may be playing a role in the regulation of mitochondrial electron transport enzyme activity, and hence perhaps mitochondrial function. This could provide a new and exciting role for TSP-1. This will require further investigation. Together, the studies in this document build upon data showing that skeletal muscle angiogenesis is a dynamic process controlled by positive and negative angiogenic proteins. It provides new and exciting evidence for the importance of negative angiogenic proteins, specifically that of TSP-1 and TSP- 2, and lays the groundwork for investigation into potential medical therapies targeting aberrant angiogenesis in skeletal muscle.

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