Aging is characterized by a decline in skeletal muscle mass and strength (sarcopenia), coupled with an accumulation of fat tissue, impairing mobility and quality of life in 45% of individuals over 65 years of age. In aged mice, the regeneration defect arises in part from a diminished regenerative capacity of resident muscle stem cells (MuSCs). The goal of this proposal is to characterize muscle stem cell subsets residing in human skeletal muscle tissue and investigate the mechanisms responsible for their regenerative defects in aging. We will capitalize on two cutting edge technologies, single-cell bioengineered stem cell niches, which will allow tracking individual muscle cell fates, and multi-dimensional single-cell mass cytometry, which will allow resolution of the molecular characteristics of skeletal muscle cells from aged humans with detail previously unattainable. We expect that this combined approach will elucidate the functional defects observed in aged MuSC populations and therefore facilitate the development of a therapeutic agent to target muscle stem cells for the treatment muscle weakness in aged humans.
The state of California is the front-runner in stem cell research, having gathered not only private investments, as demonstrated by the numerous biotechnology companies that are developing innovative tools, but also extensive public funds via Prop 71, that allows the state, through CIRM, to sponsor stem cell research in public and private institutions. In order to preserve its leadership position and encourage research on stem cells, the CIRM is calling for research proposals that could lead to significant breakthroughs or the development of technologies useful for studying stem cells in order to improve human health. Aging is characterized by a decline in tissue function and regenerative capacity that leads to degeneration and loss of muscle mass and strength (sarcopenia). Muscle stem cells (MuSCs), also known as satellite cells, are responsible for the maintenance and regeneration of skeletal muscle mass. Several studies have shown a decrease in MuSC function in aged mice. However, the mechanisms responsible for their reduced function are not yet defined. The work we propose here focuses on human muscle and discerning differences among subsets of muscle stem cells. The results will facilitate the development of targets to augment a muscle stem cell based therapy to treat muscle weakness in aged humans.
The maintenance of skeletal muscle mass throughout life depends on the action of resident muscle stem cells. This regenerative capacity diminishes as people age, leading to a decline in muscle mass and strength. The proposed research in this Fundamental Mechanisms Award proposal is based on the observation that enriched muscle stem cell populations are still heterogeneous, and it aims to identify subpopulations of cell types present within these enriched cell populations. The applicant then plans to characterize the regenerative capacity of the identified subpopulations both from young and aged humans, and to identify signaling pathways that are altered in aged muscle stem cell subpopulations. The expressed goal is to identify molecular aberrations in aged muscle stem cells that have the potential to serve as targets in future drug development efforts.
Significance and Innovation
- This is an outstanding proposal and its successful completion would lay the groundwork for the development of therapies for muscle wasting, an important unmet medical need.
- The proposed investigation employs a number of innovative, cutting edge methodologies to rigorously probe the molecular and functional differences between young and old human muscle stem cells.
Feasibility and Experimental Design
- The studies are clearly designed, logically organized and supported by strong preliminary data. All required tools are in hand.
- This project is highly ambitious and reviewers felt that not all objectives may be achieved in the given time frame. They did not consider this a critical shortcoming, as they were confident that important progress will be made.
- There was some concern that Aims 2 and 3 depend on the successful outcome of Aim 1.
Principal Investigator (PI) and Research Team
- The PI and the collaborating team are pioneers in their respective fields and are extremely well suited to conduct the proposed research.
- There was some debate as to whether the PI and a critical collaborator have committed sufficient effort to this demanding project. Some reviewers expressed concern while others were confident that this strong team, which is already assembled, will be able to deliver on this project.
Responsiveness to the RFA
- The proposed project is responsive to the RFA, it is focused on molecular and cellular mechanisms in human stem cells.