Targeting skeletal muscle to improve metabolic health in individuals with spinal cord injury

总结

SUMMARY The proposed research project examines the impact of early utilization of a novel neuromuscular electrical stimulation (NMES) program on skeletal muscle metabolism and overall metabolic health in individuals with sub-acute, complete spinal cord injuries (SCI). Background: Individuals with SCI live longer than before and live to an age where metabolic disorders become highly prevalent. Due to loss of mobility and severe skeletal muscle atrophy, obesity, glucose intolerance, and peripheral insulin resistance develop soon after the onset of SCI. These abnormalities are thought to contribute to the increased diabetes disease risk and accelerated aging process in the SCI population. As a result of these trends, overall burden of complications, economic impact and reduced quality of life are increasing. Until there are effective treatments for SCI, it is imperative to develop effective interventions to mitigate metabolic disorders that develop in individuals with SCI. There is a lack of experienced clinicians and researchers who have expertise on metabolic health and SCI. Additionally, there is a lack of adequate early interventions to prevent or reduce the degree of metabolic dysfunction that follows injury. Implications: The growing population and increased age of individuals with SCI calls for novel and interdisciplinary rehabilitation approaches to care in order to reduce the economic burden and enhance the quality of life. Next Steps: Interdisciplinary rehabilitation researchers are needed to lead the investigations necessary to address the aforementioned problems and challenges. As a candidate for this training and research proposal, I am uniquely trained and motivated to commit my career to addressing the challenges associated with the current trends. My prior research and clinical training ideally position me for an independent research career. During my doctoral and post-doctoral training, I was actively engaged in research on the development of exercise and nutrition interventions to improve musculoskeletal and metabolic health in individuals with SCI. I bring to this research a diverse training background in physical therapy and rehabilitation, human physiology, and skeletal muscle biology as indicated by my publication record. My postdoctoral experience fostered my abilities to direct truly translational research by extending clinical research experiences to mechanistic studies in skeletal muscle and molecular biology. The specific focus of my work that I will build upon involved understanding the effects of NMES on activity of intracellular signaling pathways for glucose utilization and muscle growth. I conducted all aspects of SCI projects – from subject recruitment, to clinical studies, to molecular and histological assays in the laboratory. My postdoctoral experiments revealed novel findings, some of which are detailed in the Research Strategy, providing strong support for the hypotheses of my proposal. The early results of these experiments show exciting possibilities for a quick and effective increase in insulin sensitivity and improvements in muscle phenotype in individuals with SCI who have pre-diabetes without use of medication. My enthusiasm for these findings is based on the potential for prevention. Through this work, I have found there is much work to be done and that more training in the space between disciplines (rehabilitation and metabolic disease) will enhance my effectiveness as a rehabilitation researcher. I seek an NICHD-sponsored K01 award to support investigations of a combined (resistance + aerobic) NMES training protocol for inducing physiological adaptations necessary to optimize metabolic health in individuals with sub-acute SCI. In addition, I will use the protected time for training in energy metabolism, metabolomics, and clinical trial design and implementation. These activities will ultimately prepare me for a productive, independent career focused on translating findings from basic research into feasible, clinical interventions to reduce the risk of metabolic disease in the chronic stages of SCI without use of medication. I am currently in the ideal environment to execute the proposed investigations and have assembled a mentoring team of renowned scientists in in the disciplines necessary to integrate this intervention approach. Additionally, I have access to state-of-the-art research laboratories, core facilities and equipment as well as the ability to recruit patients from a nationally recognized rehabilitation hospital. The novelty of the proposed project lies in the rigorous examination of the effects a combined (aerobic + resistance) NMES program on skeletal muscle metabolism and in the application of novel targeted metabolomics approaches to understand the influence of muscle adaptations on overall metabolic health immediately after SCI (as opposed to studying deconditioned, chronic SCI). If, as hypothesized, SCI individuals treated with a combined NMES prescription over the 6 weeks following the injury maintain a healthy muscle mass and metabolism as well as overall metabolic profile, future intervention efforts can focus on 1) preventing negative muscle adaptations in the acute stages of SCI, and 2) utilizing home-based training for life-long maintenance of overall health and quality of life.