Mechanisms of Growth and Chronic Disorders of Musculotendinous Tissues

Abstract

Musculoskeletal diseases affect over half of the United States population aged 18 or older, and over 75% of individuals 65 and older. Despite the prevalence and estimated economic burden of over $795 billion, little is known about the basic biology of some musculoskeletal tissues, nor the pathogenesis of certain musculoskeletal disorders. Understanding the biology of these tissues, as well as the mechanisms by which normal physiological functioning is lost will undoubtedly aid in the development of treatment strategies that help patients recover and return to normal life. The aims of this body of work was to i) address the lack of knowledge in basic tendon biology that restricts our ability to understand cellular and molecular changes to tendon following loading, and ii) address the mechanisms of the accumulation of pathological ectopic lipid with concomitant atrophy and fibrosis, termed myosteatosis, that occurs in chronic rotator cuff injuries. The studies in this dissertation fill in considerable gaps in the understanding of i) basic tendon biology and the role of the transcription factor, scleraxis, in adult tendon adaptation, and ii) the progression and consequences of myosteatosis on muscle metabolism and function. Scleraxis is a basic helix-loop-helix transcription factor required for the embryonic formation of tendon, but it was not known what the role of scleraxis was in adult tendon growth. We show that scleraxis is expressed in proliferative tendon fibroblasts, and is required for the proper growth and adaptation of adult tendon to mechanical stimuli. Additionally, we show scleraxis may have a critical role in the differentiation of tendon progenitor cells. For myosteatosis, it was not known how lipid accumulated within torn rotator cuff muscles, or what pathways were activated by excess lipid. We show that myosteatosis arises from an initial acute inflammatory phase marked by dysfunctional mitochondria that are unable to oxidize lipid. This results in a buildup of lipid over time, which results in a chronic, sustained inflammatory environment, marked by oxidative stress, atrophy, and muscle dysfunction. Overall, this group of studies establishes several new directions for future research that apply to a much larger body of musculoskeletal disorders.