Date of Award

Spring 1-1-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Bradley B. Olwin

Second Advisor

Leslie Leinwand

Third Advisor

Rui Yi

Fourth Advisor

William Old

Fifth Advisor

Aaron Johnson

Abstract

Skeletal muscle can regenerate to replace damaged tissue. By continuously replacing damaged tissue, muscle regeneration endows near lifelong strength and function to skeletal muscle. If skeletal muscle regeneration is impaired or ineffective, muscle function declines, which significantly increases morbidity and mortality. In fact, loss of skeletal muscle regeneration is common in many degenerative diseases, such as muscular dystrophies, myopathies and age-related muscle degeneration. It is imperative that we understand the mechanisms of skeletal muscle regeneration so that we can effectively design and develop therapies that will revitalize degenerating muscle.

My work on the mechanisms of skeletal muscle regeneration focuses on two intimately linked cell types: (1) rare, mononuclear cells with tremendous regenerative potential called muscle stem cells (MuSCs) and (2) large, multinucleated cells without regenerative potential called myofibers. When myofiber are damaged and muscle regeneration is needed, MuSCs activate and expand to form a pool of myoblast cells that then fuse to existing myofibers or fuse together to form new myofibers. How MuSC regulate the balance between making new myofibers (differentiation) and making more stem cells (self-renewal) is not fully understood. Here, we show that constitutive FGF receptor 1 signaling in MuSC during skeletal muscle regeneration increases MuSCs numbers by promoting self-renewal and impairs regeneration by blocking differentiation.We further demonstrate that constitutive FGF receptor 1 signaling in MuSC from aged muscle increases MuSC numbers and, surprisingly, restores skeletal muscle to a youthful state.

During skeletal muscle regeneration, MuSCs differentiate and fuse together to make myofibers. Myofibers are the workhorses of skeletal muscle – capable of contracting and generating force – but composed of hundreds of post-mitotic myonuclei without the ability to divide and make new myofibers. The contraction of myofibers is dependent on the sarcomere, a complex, interdigitating network of proteins. Sarcomeric proteins are translated from large mRNAs during skeletal muscle regeneration. How these large RNAs are regulated during skeletal muscle regeneration is unknown. Here we show the RNA-binding protein, TDP-43, binds mRNAs encoding sarcomeric proteins and forms cytoplasmic, amyloid-like oligomeric assemblies, termed myo-granules, during skeletal muscle regeneration in mice and humans. In healthy muscle, myo- granules are cleared as myofibers mature. Although myo-granules occur during normal muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro, and are increased in a mouse model of inclusion body myopathy. Therefore, heightened assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates common to neuromuscular disease.

Available for download on Thursday, May 13, 2021

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