Cell size is one of the most basic and defining features of a cell. However, the mechanisms controlling size are poorly understood. This is particularly true for muscle cells, which have a remarkable capacity to increase their size in response to exercise, and to decrease in size upon inactivity, aging, or disease. The long-term goal of this proposal is to define genes, mechanisms, and networks responsible for muscle size scaling under normal, hypertrophic, and atrophic conditions. These mechanisms will translate both to a better understanding of fundamental aspects required to build a functioning muscle and to better strategies for treating muscle atrophy due to aging and disease. The objective of this proposal is to define salient features of the muscle cell that determine muscle size using genetic, cell biological, mathematical modeling and imaging approaches. We will perform these studies in the Drosophila larval musculature, taking advantage of its cellular simplicity, easy readouts for cell function, optical clarity, and the availability of advanced tools for imaging and tissue-specific manipulation of genetic, environmental, and mechanical factors in vivo.
In Aim 1, we will acquire and mathematically model measurements of cell and organelle size, particularly of nuclear distribution, size/ploidy, and activity, to determine those that scale with muscle size under normal, hypertrophic and atrophic conditions. We will use this model to predict the importance of specific parameters and interrelationships between these parameters to generate functional muscle sizes. We will test our predictions by genetically manipulating the specific measured parameters. Already we have found novel compensatory mechanisms that are invoked to achieve a functioning muscle cell: nuclear area can be adjusted to account for differences in nuclear numbers in the same sized muscle.
In Aim 2, the localized effects of innervation, and the effects of mechanical forces on individual nuclei size and activity and overall cell size, will be investigated. Mechanisms responsible for altering nuclear size and activity will be uncovered. Lastly, Aim 3 will focus on the investigation of Myonuclear Domain sizes in normal, hypertrophic and atrophic muscles. We will also mathematically model and test mechanisms by which Myonuclear domains are created and maintained under normal, hypertrophic and atrophic conditions. Altogether, these experimental and computational approaches will identify defining parameters of muscle cell size under normal, hypertrophic and atrophic conditions, and their physiological range required for muscle function. These data 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.
Muscle cells have a remarkable capacity to increase their size in response to exercise, and to decrease size upon inactivity, aging, or disease. Despite the fundamental importance of muscle cell size to its function and the corresponding scaling up or down of the muscle cell's organelles during normal development, homeostasis and in disease, the mechanisms that regulate muscle cell size scaling are poorly understood. We will quantify and mathematically model the different aspects of cell size in normal, hypertrophic and atrophic conditions, determine how these integrate with neural activity and mechanical forces, and finally determine the relationships between cell size and myonuclear domains both in vivo and on a single cell level.
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