Sizing and Scaling in Functional Muscle Cells

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Project Summary/Abstract The mission of the Baylies lab is to deliver basic research findings that will support better therapies across a range of muscle diseases. Our goals are the identification of genes and mechanisms that are essential for the formation and healthy functioning of skeletal muscle, and where these mechanisms go awry in disease states such as muscular disorders (nemaline and centronuclear myopathies), muscle wasting (cachexia, aging), and soft tissue cancer (rhabdomyosarcoma). Specifically, the lab aims to understand key processes that lead to skeletal muscle: cell fate commitment, cell-cell fusion, movement and positioning of organelles such as the nucleus, and muscle fiber growth and maturation. That research is conducted by developing and combining novel genetic, cell biological, imaging, molecular and mathematical approaches, using Drosophila and mammalian muscle cells. Our current investigations focus on a fundamental question: what determines muscle cell size? The mechanisms that control cell size are poorly understood. This is particularly true for a skeletal muscle cell, which may have hundreds of nuclei and is among the largest cells in the human body. Skeletal muscle cells have a remarkable capacity to increase their size in response to exercise (hypertrophy), and to decrease in size upon inactivity, aging, or disease (atrophy). Our work in Drosophila has revealed critical nuclear parameters (number, DNA content, size, activity) that can each be adjusted and coordinated by the muscle cell to generate a particular size. We have also found that the many nuclei in a muscle cell vary in number and activity along the length of a muscle fiber. Key questions we are pursuing over the next five years include: How does a muscle cell generates these regional differences yet globally coordinate the nuclei within a single cell? Are such differences apparent in other organelles? Similarly, what are the specific signals and mechanisms that establish and maintain nuclear identity along the muscle cell; what are the contributions of each nucleus to their local cytoplasmic domain and to the entire muscle cell? How does each nucleus set up its cytoplasmic area and are there regional differences? Finally, under conditions of hypertrophy or atrophy, how are nuclear and cytoplasmic identities and the compensation/communication mechanisms impacted? Altogether, our work will identify defining parameters of muscle cell size under normal, hypertrophic and atrophic conditions, and their physiological range required for muscle function. Our studies will reveal general principles of cell size regulation, provide insight to how improper regulation of these processes results in disease, and inform regenerative medicine aimed at muscle.