In space, cardiac muscle weakens because it does not have to work against the force of gravity. Dr. Beverly H. Lorell is studying the cellular and molecular mechanisms involved in this atrophy and the functional consequences of these changes. The work is leading to the identification of countermeasures to preserve cardiac mass and function.
Cardiac Unloading: Biologic Mechanisms and Countermeasures for Cardiac Atrophy
Beverly H. Lorell, M.D.
Harvard - Beth Israel Deaconess Medical Center
The aims of the project are to determine functional consequences of cardiac remodeling due to microgravitational unloading using earth-based model of heterotopic transplantation. The following biologic effects of this surrogate model of cardiac unloading will be examined:
- Effects on adult myocyte contractile function and Ca2+ regulation
- Regulation of myocyte growth and programmed cell death (apoptosis)
- Identification of human-relevant countermeasures which blunt cardiac atrophy and/or enhance functional cardiac reserve (including alpha-adrenergic agents).
The key findings of the project to date are the following:
- Using the heterotopic transplant model of cardiac unloading, we made three observations:
- Cardiac unloading modifies contractile reserve of cardiac myocytes, ie, the ability of heart muscle cells to do extra work.
- The biologic mechanism is related to a distinct "molecular signature" the expression of Ca2+ regulatory genes in the heart.
- The changes are related to magnitude and duration of unloading. These observations have direct implications for planning future human studies, and suggest that lessons from short-term spaceflight may not necessarily predict biologic effects of long-term spaceflight in the hearts of astronauts.
- Using genetic mouse models, two novel pathways for preservation of cardiac mass and function have been identified:
- Cyclin-dependent kinase-9 pathway
- Telomerase reverse transcriptase pathway.
The key findings of the project to date directly confirm the hypothesis of specific aim 1: Cardiac unloading does affect both cardiac myocyte contractile function and Ca2+ regulation.