BRC-BIO: Cell cycle regulators in postmitotic multinucleated cells: Conserved mechanisms regulating muscle cell size.

Cell growth is closely linked to cell division; to meet the demands of growth, cells must increase protein synthesis. The synthesis of new ribosomes (which make proteins) plays a crucial role in supporting the increased protein synthesis required during the cell cycle and division to make new cells. However, the role of the synthesis of new ribosomes in cells that are fully matured and incapable of cell division remains much less clear.

Mature skeletal muscle cells are differentiated cells, meaning that they cannot undergo cell division anymore; yet several proteins typically associated with the cell cycle are expressed in skeletal muscle cells, even though they will never divide. This research project will investigate the roles of proteins responsible for cell cycle progression in non-dividing cells, such as mature muscle cells, in particular the synthesis of new ribosomes.

Using novel genetically modified mouse models, the researchers will manipulate the cell cycle to explore the effects slowing or speeding up the cell cycle on ribosome production and muscle cell size. Undergraduate students working from the Principal Investigator’s lab, and from a new Course-Based Undergraduate Research Experience (CURE), will receive extensive training on muscle biology while supporting this project.

While cell cycle progression has been extensively studied in proliferative cells, the role of cell cycle regulators in postmitotic cells remains unclear. Fully differentiated skeletal muscle cells can express several cell cycle regulators that are key to ribosome biogenesis – a cellular process where we hypothesize that the role of these regulators is conserved in postmitotic cells.

This research aims to investigate the role of cell cycle regulators in mature skeletal muscle cells, focusing primarily at the level of the Cyclin-Dependent Kinase 4 (CDK4), a central kinase regulating ribosome biogenesis in proliferative cells. Specifically, this study will: 1) Determine whether CDK4 regulates muscle ribosome biogenesis and muscle cell size, and; 2) Test whether promoting cell cycle progression via a constitutively active CDK4 in differentiated muscle cells causes the muscle progenitor cells, known as satellite cells, to fuse with the mature myofibers.

To address these questions, the PI, graduate, and undergraduate researchers will use genetically modified mouse models to specifically and conditionally knock out or overexpress key regulators of the cell cycle, such as CDK4, in mature myonuclei. If the hypothesis is correct, the results from this proposal will represent a paradigm shift in our understanding of the role of cell cycle in terminally differentiated cells, such as muscle cells.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.