The candidate is a biomedical engineer with expertise in mass transport phenomena and metabolic modeling. His goal is to become an investigator in the field of multi-scale systems biology that combines computational modeling and experimental methods. Through advanced methodology, he will quantify mechanisms relating cellular metabolism to physiological responses in health and state disease. The training award provides a formal framework in which the candidate can gain fundamental knowledge of energy metabolism and muscle biology together with experimental techniques. The proposed plan includes in vitro and in vivo studies as well as related courses in biomedical sciences. The research training emphasizes quantitative understanding of the regulation of cellular energy transfer and metabolism in myocyte and whole skeletal muscle in response to energy demand in control and diabetic rats. Biochemical properties and bioenergetic function of cytosol and mitochondria will be characterized in control and diabetic myocytes. Also, NMR measurements of metabolites within the skeletal muscle will be used to study adaptive changes to different stimuli. The mentored research training has the necessary multi-disciplinary components that include a primary mentor with expertise in mitochondria energetics and a co-mentor with expertise in NMR techniques and metabolism. These mentors will lead an Advisory Committee of investigators with expertise in a) computational modeling of metabolic and physiological systems;b) exercise and insulin resistance in skeletal muscle;c) skeletal muscle fatigue and metabolism. Type 2 diabetes mellitus cause functional adaptations in skeletal muscle in which insulin resistance (IR) is co-expressed by a higher ratio of glycolytic to oxidative capacities. Inadequate coordination between cytosolic and mitochondrial functions may be one mechanism that limits insulin-stimulated glucose utilization. However, the cause-and-effect relationship between mitochondria dysfunction and IR is not defined. This dysfunction may be related to reduced mitochondrial content rather than intrinsic defects or altered metabolic regulation. Possible mechanisms relating amelioration of IR to changes of mitochondria content, mitochondria oxidative function, or membrane transporter function will be evaluated using exercise training. In the proposed plan, the importance of these mechanisms will be evaluated by quantifying the effects of exercise training. The measured responses to muscle contraction or insulin stimulations will include changes in biochemical and biotransport properties as well as bioenergetic functions of the oxidative and glycolytic systems in cytosol and mitochondria. The proposed study combines in vitro and in vivo experiments with mechanistic computational models of skeletal muscle energy metabolism to investigate mechanisms of muscle metabolic dysfunction in diabetes. Simulations with the validated computational models will help to identify hypotheses that can be tested with efficient experimental designs.

Public Health Relevance

In diabetic patients, abnormal energy metabolism of skeletal muscle energy metabolism compromises the quality of life. The goal of this research project is (a) to quantify the key factors responsible for metabolic and mitochondrial dysfunction in diabetes and (b) to elucidate the impact of exercise training on energy metabolism. Data from a unique combination of cellular, mitochondria, and animal model experiments will be obtained and analyzed using a mechanistic, computational model of skeletal muscle energy metabolism.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Quantitative Research Career Development Award (K25)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Boyce, Amanda T
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Case Western Reserve University
Biomedical Engineering
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United States
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Lai, Nicola; M Kummitha, China; Rosca, Mariana G et al. (2018) Isolation of mitochondrial subpopulations from skeletal muscle: Optimizing recovery and preserving integrity. Acta Physiol (Oxf) :e13182
Lai, Nicola; Kummitha, China; Hoppel, Charles (2017) Defects in skeletal muscle subsarcolemmal mitochondria in a non-obese model of type 2 diabetes mellitus. PLoS One 12:e0183978
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Spires, Jessica; Gladden, L Bruce; Grassi, Bruno et al. (2012) Model analysis of the relationship between intracellular PO2 and energy demand in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 303:R1110-26