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Copyright by Geoffrey Josef Solares 2019 The Dissertation Committee for Geoffrey Josef Solares Certifies that this is the approved version of the following Dissertation: ACUTE AND CHRONIC EFFECTS OF b-HYDROXY-b- METHYLBUTYRATE (b-HMB) ON GLUCOSE TOLERANCE, INSULIN SENSITIVITY AND MUSCLE ADAPTATION FOLLOWING CHRONIC RESISTANCE TRAINING Committee: Roger P. Farrar, Co-Supervisor Laura J. Suggs, Co-Supervisor Molly S. Bray Richard E. Wilcox Janice S. Todd ACUTE AND CHRONIC EFFECTS OF b-HYDROXY-b- METHYLBUTYRATE (b-HMB) ON GLUCOSE TOLERANCE, INSULIN SENSITIVITY AND MUSCLE ADAPTATION FOLLOWING CHRONIC RESISTANCE TRAINING by Geoffrey Josef Solares Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May 2019 Acknowledgements There have been many people who have contributed to my dissertation for whom I owe a debt of gratitude. First and foremost, I would like to thank my advisor Dr. Roger Farrar. Roger, you have without a doubt been an invaluable asset to me as a researcher and as a young man, husband, and father, who had a mentor which sought to ensure that his mentee was able to feed their growing family with a steady supply of good teaching assistant jobs. No amount of words here can express that fact, Rog, I owe more than I could ever repay you. I would also like to thank my initial advisor, Dr. John Ivy for his wisdom and perspective relating to my development as a more robust researcher. Also, you have taught me a mentoring style that forces the person to persevere and develop internal reflections paramount to a quality researcher. In essence John, you re-enforced the idea of “grit” an idea that appears to be waning nowadays. I would also like to thank Dr. Richard Wilcox for your endless critiques to this manuscripts and encouragement to “go big or go home” when designing my experiment. I would like to thank Dr. Molly Bray. Molly, working with you over the past years as your teaching assistant and in your lab, you graciously welcomed me to a different environment and fostered a profound amount of critical thinking in me, I thank you. iv To Wenbai Huang for is constant aid and support throughout all of our early mornings and long afternoons as we worked to complete my resistance exercise protocol and animal surgeries, I thank you. To my siblings, Giorgio, Krystal, and Briahna, thank you for making me feel less disconnected from life back in California. I would especially like to thank my parents, who over the years have greatly helped me establish myself and my wife in Austin and who been a bastion of unconditional love throughout my entire life. To my parents who have countless times provoked my thinking, re-shaped my viewpoints, as well as forever placing on me the emphasis that knowledge opens doors and instilling “grit” at an early age. I would not be here without your help. I love you both! I would also like to express my gratitude to my extended family. Chuck and Sue, you have always been there for me and even hosted my family for weeks at a time whenever we arrived in town in addition to the support you gave Amy when she needed a call or longed for home you both were always there, I am eternally grateful. Finally, to my wife and sons. Amy, I know I dragged you out here right after our wedding and the years have been a roller-coaster of a ride, but it has been a ride I would have shared with no one else. For making our apartments and house a home, warm meals, cuddles on the couch, giggles, and for growing, having, and teaching our three beautiful sons with endless love, these words do not scratch the surface of how I feel for you, I love you. While this dissertation represents my work at UT, it fails to reflect all the work you did to make this dissertation complete. Your name belongs aside mine on the diploma for all the exams, presentations, and work you helped me with throughout our time at UT. v Jackson, my son, your smiles, laughter, and innocence are infectious and have been a blessing since the moment I got to hold you and say “my boy”. Getting to hear every single time I come through the door, “Momma, Dada’s home”, you will never know how much that makes my heart swell. Never change my son. Kylar, your serenity in looking at the raucousness that can be our home life reminds me to live life in the moment and take it all in. Thank you for choosing our family and letting me be your dad. Logan, while you arrived late in the game, you have been awaited with as much joy as a father could have for their son. Your coos and giggles while I wrote this dissertation are heartwarming memories and remind me why I went through all of this - for each of my boys to be inspired. Jackson, Kylar, and Logan, your growth in our home has been a joy I cannot imagine living without, never forget my sons, Dada loves you. vi ACUTE AND CHRONIC EFFECTS OF b-HYDROXY-b- METHYLBUTYRATE (b-HMB) ON GLUCOSE TOLERANCE, INSULIN SENSITIVITY AND MUSCLE ADAPTATION FOLLOWING CHRONIC RESISTANCE TRAINING Geoffrey Josef Solares, Ph.D. The University of Texas at Austin, 2019 Supervisors: Roger P. Farrar & Laura J. Suggs Maximizing protein accretion and mitigating protein degradation is a major goal for resistance training regimens and intervention therapies. The branch chain amino acid leucine has historically demonstrated a significant role in the activation of protein synthesis via the activation of the mammalian target of rapamycin complex 1 (mTORC1). A derivative of leucine metabolism, beta-hydroxy-beta-methylbutyrate (HMB) has shown similar effects on mTORC1 with recent literature suggesting adverse effects of HMB on glucose homeostasis and regulation. Herein, we used animal models to test the effects of varying doses of HMB on glucose homeostasis during a novel chronic resistance whole body training model. These data suggest that HMB effects cause acute modulation to the Akt/mTOR signaling pathway proteins, with minimal contributions to strength gains during chronic resistance whole body exercise. Our novel whole body exercise technique revealed a significant increase in strength gains with no differences in in situ force production in quadriceps and triceps surae muscle groups, but did show increased force per unit mass in both the triceps surae and quadriceps muscle groups. These data suggest an increase in whole body muscular coordination and/or synchronicity in force production that promotes increases in overall total strength. Furthermore, our data suggests that the overload placed on each individual contributing muscle to force vii output was not significant enough to induce a hypertrophic response. We conclude that HMB ingestion provides minimal benefit during prolonged exercise regimens and the effects of HMB on blood glucose and insulin sensitivity are not adverse. Finally, our whole body resistance model presents a novel paradigm for increasing work output that can be a model of whole body resistance training. viii Table of Contents List of Tables ................................................................................................................ xii List of Figures .............................................................................................................. xiii CHAPTER I:GENERAL INTRODUCTION ................................................................... 1 Blood glucose regulation............................................................................. 1 Signaling pathways which control blood glucose ........................................ 1 Resistance exercise increases hypertrophy via mTOR activation ................. 3 Timely nutritional intervention reduces proteolysis ..................................... 4 OBJECTIVES ........................................................................................................ 4 HYPOTHESES ...................................................................................................... 5 Study 1 ....................................................................................................... 5 Study 2 ....................................................................................................... 5 Study 3 ....................................................................................................... 6 SIGNIFICANCE .................................................................................................... 6 LIMITATIONS ...................................................................................................... 7 CHAPTER II: LITERATURE REVIEW ......................................................................... 9 BETA-HYDROXY-BETA-METHYLBUTYRATE (b-HMB) .................... 9 Safety of ß-HMB .............................................................................. 10 INSULIN SIGNALING ............................................................................ 11 Akt/PKB activation, targets, and downstream effects ........................ 13 MUSCLE PROTEIN SYNTHESIS SIGNALING PATHWAYS............... 14 How resistance exercise affects protein turnover .............................. 17 How b-HMB interacts with protein turnover .................................... 21 ix MUSCLE PROTEIN DEGRADATION SIGNALING PATHWAYS ....... 23 How b-HMB interacts with the muscle protein degradation pathways .................................................................................... 25 MUSCLE ADAPTATION TO RESISTANCE EXERCISE ....................