Nuclear Pore Complexes in the Maintenance of Skeletal Muscle Integrity and Function
Abstract
In adulthood, muscle growth and maintenance require the constant regeneration of muscle fibers. As we age or in pathological conditions, the deterioration of mechanisms that maintain muscle homeostasis results in the loss of muscle mass and reduced muscle repair. This can lead to the slow recovery of muscle after injury, to decreased muscle performance, and to the development of muscle diseases such as muscular dystrophies. The reduction of skeletal muscle mass and strength leads to weakness, physical disability, and declined mobility, decreasing the quality of life and increasing morbidity. Identifying and characterizing the factors and mechanisms involved in the maintenance of skeletal muscle tissue are crucial to the development of therapies that can improve muscle repair and prevent the degeneration of muscle integrity. In eukaryotic cells, the genome is enclosed in an organelle known as the nucleus, which acts as the cell’s control center. The doors of the nucleus are large multiprotein channels known as nuclear pore complexes or NPCs. These channels act as the gatekeepers that regulate the entrance and exit of all molecules in and out of the nucleus. In addition, NPCs perform other functions such as regulating the activity of muscle genes. We previously identified that one NPC component, known as Nup210, plays a key role in the maintenance of muscle physiology. We uncovered that Nup210 regulates muscle repair and the growth and survival of muscle cells. More recently, we generated a mouse model that lacks Nup210 and established that these animals show a deterioration of muscle integrity with age that shares many features of inflammatory myopathies. More importantly, we identified that increasing the levels of this components in muscle progenitors promotes their conversion into muscle cells and can also rescue some muscle defects associated with muscles dystrophies. Our findings exposed for the first time a role for NPCs in the regulation of muscle physiology and allow us to propose the exciting possibility that modulating the activity of these complexes through Nup210 could potentially be exploited to enhance muscle function and repair. In this proposal, we seek to use a combination of genetic mouse models for Nup210 and Duchenne Muscular Dystrophy to characterize in detail the functions of this NPC component in the maintenance of skeletal muscle integrity, and to investigate if increasing its activity can promote muscle regeneration and improve muscle endurance. We expect our work to significantly advance our knowledge of the regulation of muscle homeostasis and could represent the first step in the development of novel pharmacological strategies for the treatment of muscle disorders. Our proposal relates to the Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Areas Musculoskeletal Disorders and Tissue Regeneration and the following Area of Encouragement: Development of novel therapies for regeneration of functional skeletal muscle, particularly (1) stem cell-based approaches and (2) treatments for volumetric muscle loss. In the short term, our work will increase our understanding of the basic mechanisms that regulate the maintenance and repair of skeletal muscle tissue. This knowledge critically underpins our ability to diagnose, understand, and treat muscle disorders. Currently, there is no cure for muscular dystrophies and there is an urgent need for new treatments that can improve the life of patients suffering from these devastating diseases. Our proposal will investigate for the first time the potential of improving skeletal muscle function/regeneration by manipulating the levels of Nup210. In the long term, these findings could lead to the development of novel clinical approaches that could enhance muscle function and could lead to novel therapeutic strategies to treat specific muscle dystrophies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010212
Entities
People
- Maximiliano D Angelo
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army