An exploration of the mechanisms of naturally occurring limb muscle loss during neonatal development

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Millions of Americans are impacted by muscle loss – as an effect of disease, injury, or aging – and yet there is currently no cure for any form of muscle degeneration. Consistent with the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, it is therefore essential to understand muscle development and degeneration in the broadest context. The Cooper lab has identified naturally occurring muscle loss during development of a bipedal desert rodent, the lesser Egyptian jerboa. Aspects of the cellular process, which occurs early and rapidly after birth of the animal, defy predictions based on decades of muscle research in traditional model organisms and highlight gaps in the current state of understanding. Most surprising, despite the rapid and complete loss of muscle structural protein expression, there is no detectable evidence of cell death or an immune response in the jerboa foot. Early stages of muscle maturation appear to proceed normally, but nascent muscle structure subsequently disassembles by an as yet unknown mechanism. Muscle progenitor cells persist until late in the phase of muscle cell loss, but they are insufficient to restore muscle. A deep understanding of this remarkable phenotype stands to transform our understanding of the cellular and molecular mechanisms of sarcomere disassembly and to potentially identify unexpected developmental plasticity of neonatal muscle cells. Specifically, the First Aim will address the perplexing observation that no characteristic features of multiple mechanisms of cell death are detected concurrent with widespread and rapid muscle cell loss. We will apply an electroporation-mediated cell tracking approach to follow the fate of the muscle lineage after muscle cells can no longer be identified by expression of muscle proteins. The Second Aim will implement an RNA sequencing approach to identify the cellular and molecular processes unfolding at the initiation of muscle loss. Each Aim investigates an aspect of jerboa foot muscle cell loss that potentially intersects with human muscle degenerative disorders yet here occurs in the context of normal development of the organism. The experiments outlined in this proposal are essential first steps toward a broader goal of understanding the molecular mechanisms that underlie the striking anatomic specificity of hindfoot muscle loss in the jerboa. Since the fundamentals of cell and tissue function are conserved across species, or indeed traditional model organisms would have no value, answers to the questions outlined in this proposal will inspire explorations of new dimensions of cell biology in a variety of tissues and contexts.