Sizing and Scaling in Functional Muscle Cells

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.

Grant Number: 5R35GM141877-05
NIH Institute/Center: NIH
Principal Investigator: MARY BAYLIES