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The Effect of a Ketogenic Diet on Mitochondria Function in Human Skeletal Muscle During

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The Effect of a Ketogenic Diet on Mitochondria Function in Human Skeletal Muscle During The effect of a ketogenic diet on mitochondria function in human skeletal muscle during adaptation to chronic exercise training and the potential involvement of metabolic dysregulation Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Vincent J. Miller, MS Ohio State University Nutrition Program The Ohio State University 2019 Dissertation Committee Jeff S. Volek, PhD, RD, Advisor William J. Kraemer, PhD W. David Arnold, MD Frederick A. Villamena, PhD Copyrighted by Vincent J. Miller 2019 2 Abstract Objective: The prominent influence of skeletal muscle mitochondria on health and physical capacity can be enhanced through diet and exercise. Ketogenic diets have great potential to drive this enhancement, but prior research is limited, particularly in humans. Therefore, the objective of the present research was to characterize changes in skeletal muscle mitochondria function induced by a ketogenic diet during adaptation to chronic exercise. Methods: Twenty-nine participants completed a 12-week supervised exercise program while following a ketogenic diet (KD, n=15, males=13) or their habitual mixed diet (MD, n=14, males=12). Body composition was measured using dual-energy x-ray absorptiometry (iDXA, GE Healthcare, Chicago, IL). Blood was drawn in a fasted and resting state and serum insulin and glucose were measured using an enzyme-linked immunosorbent assay kit (Calbiotech, El Cajon, CA) and a hexokinase reagent set (Pointe Scientific, Canton, MI), respectively. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated based on insulin and glucose values. Respiratory quotient (RQ) was measured through gas exchange (TruOne 2400, Parvo Medics, Sandy, UT). Muscle biopsies were collected from the Vastus lateralis, from which mitochondria were isolated. O2 consumption and membrane potential were measured with a Clark-type electrode fitted with a tetraphenylphosphonium electrode. H2O2 and ATP production were measured using fluorescence (Amplex Ultra Red) and luminescence (luciferase) assays, respectively. Each test was repeated with a carbohydrate- (pyruvate), fat- (palmitoyl-L-carnitine), and ketone-based (β- ii hydroxybutyrate+acetoacetate) substrate. Results: Participants were matched by age, gender, and body fat (KD vs MD: 27.4±1.8 vs 24.6±2.4 yrs, 25.6±1.3% vs 22.0±2.3%). At baseline, HOMA- IR was greater in KD (2.1±0.3 vs 1.5±0.2, p=0.056) and decreased during the intervention (2.11±0.3 to 1.11±0.1, p=0.008). Weight loss was greater for KD (-6.9±0.9 vs 0.7±0.4 kg, p<0.001), as was decrease in body fat percentage (-5.4±0.7 vs -0.7±0.5 %, p<0.001). Mean daily blood β-hydroxybutyrate concentration for KD was 1.2±0.2 mM and RQ decreased only in KD (0.82 to 0.75, p=0.001), all indicating the ketogenic diet induced a profound shift in energy metabolism towards reliance on fat oxidation. An effect of time was observed for increases in mitochondrial protein (p=0.019) and respiratory control ratio (RCR, p=0.003). Time by diet interactions indicate a lesser increase in H2O2 (p=0.098) and a relative increase in ATP production (p=0.003) and efficiency (based on ATP/O2 and ATP/H2O2, p<0.005) for KD. With the fat-based substrate, RCR and ATP production increased only for KD (4.7±0.3 to 5.6±0.2, p=0.009; 20.9±4.2 to 28.4±4.6 nmol/mg/min, p=0.028). ATP production with the ketone-based substrate was 4 to 8 times lower than with other substrates, indicating that ketones are minimally oxidized in human skeletal muscle. Conclusions: While the effects of time for mitochondrial protein and RCR indicate exercise-induced enhancement of mitochondria function, the time by diet interactions for ATP, ATP/O2, and ATP/H2O2 indicate augmentation of this enhancement by the ketogenic diet, particularly in relation to fat oxidation. The improvement in HOMA-IR for KD suggests that these improvements may have partly been related to rescue of metabolic impairment. Further research is strongly encouraged for determination of mitochondria function as a target through which ketogenic diets improve metabolic health. iii Dedication Dad, you always wanted me to be a doctor, and even though you meant the other kind of doctor, I know without a doubt there is nobody who would be more proud. I will be forever grateful for everything you have done for me and your memory will forever inspire me to live my life in a way that would make you proud and to help others avoid what stole your brilliant mind. I miss you dearly. 49! iv Acknowledgments A variety of people have made the research in this dissertation possible by providing critical contributions, directly supporting my work, or by influencing my path towards pursuing a PhD. I would like to acknowledge my sincere appreciation to each of these individuals. Thank you, Mr. Mandracchia, for inspiring me to care about education. Your interest in my ability was the turning point that converted me from an apathetical high-school student to an avid, life-long learner. Thank you, Mom, for always believing in me, for pushing me to be the best I can be, and for giving me the gift of persistence. Thank you, Kayla, for understanding and gracefully accepting the sacrifices involved in this process. As much as I have tried to teach and demonstrate to you the meaning of good character, you continue to teach me instead. Thank you, Kim, for standing by me for the past two decades. Actions speak louder than words and the sacrifices you have made on my behalf speak volumes. Even when you think my ideas are extreme or obsessive, which they often are, you still support me. Thank you, Dr. Sarah Everman, for helping me through the decision to pursue a PhD, and thank you, Dr. Paul Arciero, for welcoming me into your lab to gain research experience. I consider you both friends as much as mentors. Each of you were instrumental in helping me get to this point and I will always be grateful. v Thank you, Dr. Jon Parquette, for allowing me to use your freeze dryer, and thank you, Cassidy Creemer, for your assistance. Thank you, Jacquie Stewart and Dr. Eric England, for providing me with the animal tissue needed to develop the mitochondria assays that are the foundation of this research. Thank you to my labmates for your support and assistance, especially Rich LaFountain for co-leading this study with me and Emily Barnhart for supervising the exercise training. Thank you to our study participants who graciously subjected themselves to the muscle biopsies that made this research possible. Finally, thank you to my committee members, each of whom supported me throughout this project and helped to make it the best it could be. Dr. Villamena, thank you for sharing your expertise on oxidative stress. The knowledge I gained from your outstanding course greatly enhanced this project and your support exemplifies the benefit of the interdisciplinary nature of the OSUN program. Dr. Arnold, thank you for enabling this research to be a reality! The possibility of not finding a physician to perform muscle biopsies was close to becoming a very disappointing reality until you saved the day and managed to fit us into your busy schedule. My involvement with the biopsy procedure was an unexpected experience that turned out to be one of my best memories from this project. Thank you also for your support with other areas of the project and for the opportunities you have given me to expand my research exposure. Although I was unable to follow through with our plans for the motor neuron study, I enjoyed collaborating with you and very much appreciate the opportunities to analyze spinal cord mitochondria and gain exposure to animal research. vi Dr. Kraemer, thank you for inspiring me to better understand the implications of mitochondria localization in the myocyte and for expanding my knowledge of endocrinology. I came to Ohio State excited about the prospect of working with you and maintaining kinesiology as part of my focus on nutrition. Having the opportunity to interact with you and your team has been both a pleasure and a privilege. I am grateful for all of your support and honored to have you as a member of my committee. Dr. Volek, you have been the driving force behind this life-changing process and I will forever be grateful for your wise guidance and generous support. You invited me into your lab despite my limited research experience, and you fully supported my interest in mitochondria research despite it being a complex and completely new area of focus within our team. The sacrifices I made and imposed on my family to pursue a PhD came with tremendous pressure, but the work that you enabled me to do confirms that I made the right choice. Your appreciation for genuine academic pursuit is highly admirable. I feel privileged to have benefited from it and am very proud of having contributed to your mission of advancing scientific understanding of nutritional ketosis and its potential to benefit public health (and service). vii Vita 1993 ……………….. Carmel High School 1997 ……………….. BS Mechanical Engineering, Rensselaer Polytechnic Institute 2012 ……………….. MS Human Nutrition, University of Bridgeport 2014 ……………….. MS Human Movement/Kinesiology, A. T. Still University 2015 to present ……. PhD Ohio State University Nutrition, The Ohio State University Publications LaFoundtain, R. A., Miller, V. J., Barnhart, E. C., Hyde, P. N., Crabtree, C. D., McSwiney, F. T., . Volek, J. S. Extended ketogenic diet and physical training intervention in military personnel.
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