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The Role of Growth Hormone in the Regulation of the Anaerobic Energy System and Physical Function Viral Chikani MBBS, FRACP

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The Role of Growth Hormone in the Regulation of the Anaerobic Energy System and Physical Function Viral Chikani MBBS, FRACP The Role of Growth Hormone in the Regulation of the Anaerobic Energy System and Physical Function Viral Chikani MBBS, FRACP A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2016 School of Medicine Abstract Growth hormone (GH) regulates energy metabolism and body composition in adult life. Adults with GH deficiency (GHD) suffer from lack of energy and from impaired physical functioning. GH supplementation improves sprinting in recreational athletes, a performance measure dependent on the anaerobic energy system (AES). The AES underpins the initiation of all physical activities including those of daily living. The physiological and functional significance of GH in regulation of the AES is unknown. This thesis tests the hypothesis that GH positively regulates the AES and aspects of physical functioning in adult life. The key objectives are to 1) investigate whether anaerobic capacity is impaired in adults with GHD and improved by GH replacement, ii) characterise facets of physical function that are AES-dependent and GH responsive and iii) identify GH-regulated genes governing anaerobic metabolism in skeletal muscle. Exercise capacity, body composition, physical function and quality of life (QoL) were studied in 19 adults with GHD before and after GH replacement. Anaerobic capacity was assessed by the 30- second Wingate test, and aerobic capacity by the VO2max test. Physical function was assessed by the stair-climb test, chair-stand test, and 7-day pedometry. QoL was assessed by a GHD-specific questionnaire. Lean body mass (LBM) was quantified by dual-energy x-ray absorptiometry. Muscle biopsies were obtained before and after 1 and 6 months of GH replacement. GH responsive genes were identified by microarray analysis. In a cross-sectional study, anaerobic capacity and aerobic capacity were significantly reduced compared to age-, gender- and body mass index-matched normal adults. The duration of the stair climb test was longer, the number of chair stand repetitions and daily step counts were lower in adults with GHD who had lower QoL scores. GH status was an independent predictor of anaerobic capacity, which significantly and independently correlated with stair climb performance and QoL. One month of GH replacement (0.5 mg/day) did not significantly change anaerobic capacity nor any of the other outcome measures compared to placebo in adults with GHD. Six months of GH treatment significantly increased LBM, anaerobic capacity, chair-stand repetitions, daily step count, and QoL scores but not VO2max. Improvement in anaerobic capacity significantly correlated with an improvement in the energy and vitality domains of QoL. GH treatment did not significantly affect the differential expression of metabolic genes in skeletal muscle. In summary, anaerobic capacity, aerobic capacity, physical function and QoL were impaired in adults with GHD. GH replacement improved anaerobic capacity, LBM, chair-stand performance, daily step counts and QoL in a time-dependent manner without a concomitant improvement in aerobic capacity. GH at a replacement dose was insufficient to induce the detection of GH-regulated genes governing substrate metabolism and energy production in skeletal muscle. In conclusion, GH positively regulates the AES, which improves selective aspects of physical function influencing QoL in adult humans. Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. Publications during candidature Publications: Chikani V, Cuneo RC, Hickman I, Ho KK. 2016 GH enhances anaerobic capacity: Impact on physical function and quality of life in adults with GH deficiency. Clin Endocrinol (Oxf). doi:10.1111/cen.13147 Chikani V, Cuneo RC, Hickman I, Ho KK. 2015 Impairment of anaerobic capacity in adults with growth hormone deficiency. J Clin Endocrinol Metab 100:1811-1818 Chikani V, Ho KK. 2014 Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J Mol Endocrinol 52:R107-123 Conference Abstracts: Chikani V, Cuneo RC, Hickman I, Ho KK. Effects of GH replacement on Anaerobic Capacity in Adults with GHD. Endocrine Society of Australia Annual Scientific Meeting, Adelaide 2015 Chikani V, Cuneo RC, Hickman I, Ho KK. Growth Hormone therapy improves Anaerobic Exercise Capacity and Physical Function in Adults with Growth Hormone Deficiency. The Endocrine Society Annual Scientific Meeting, San Diego, USA 2015; FRI-446 Chikani V, Cuneo RC, Hickman I, Ho KK. Impairment of Anaerobic Capacity in Adults with Growth Hormone Deficiency.’ 7th International Congress of the GRS and IGF Society, Singapore 2014 Chikani V, Cuneo RC, Hickman I, Ho KK. Effects of Growth Hormone on Anaerobic Capacity in Adults with Growth Hormone Deficiency: A Double-Blind Placebo-Controlled Trial. Endocrine Society of Australia Annual Scientific Meeting, Melbourne 2014 Chikani V, Cuneo RC, Hickman I, Ho KK. Growth hormone regulation of muscle function: Role of the Anaerobic Energy System. The Endocrine Society Annual Scientific Meeting, Chicago, USA 2014; MON-673 Chikani V, Cuneo RC, Hickman I, Ho KK. Growth hormone action on muscle function: role of the anaerobic energy system. Endocrine Society of Australia Annual Scientific Meeting, Sydney 2013 Publications included in this thesis No publications included. Contributions by others to the thesis I performed RNA extraction from muscle tissue under supervision of Dr. Johanna Barclay and Dr. Chris Morais. I performed qRT PCR experiments under supervision of Dr. Caroline Nelson. I performed statistical analysis of the data under guidance of Dr. Anne Bernard and bioinformatics analysis of microarray data under guidance of Dr. Stephen Rudd, Queensland Facility for Advanced Bioinformatics. Statement of parts of the thesis submitted to qualify for the award of another degree None. Acknowledgements I would like to sincerely thank my supervisor, Professor Ken Ho for his guidance and support through out this degree. He has been a great teacher and mentor to me. I’d also like to thank Dr Ross Cuneo, my secondary supervisor for always being available to help and provide advice whenever needed. I would like to thank the Princess Alexandra Research Foundation for providing a postgraduate scholarship and NovoNordisk for providing growth hormone and placebo to undertake this research project. I am indebted to my research nurse Ms Tracy Grierson, who helped me with the clinical studies. The assistance from the Dr Caroline Nelson with the laboratory techniques and Dr Anne Bernard with statistical analysis has been invaluable. I am grateful to Associate Professors Tony Russell and Warrick Inder, for their continual encouragement and support throughout this period. Finally, I would like to thank my wife and my parents, without their unconditional and tireless support this would never have been possible. Keywords Growth hormone deficiency, energy metabolism, anaerobic energy system, exercise capacity, muscle function Australian and New Zealand Standard Research Classifications (ANZSRC) ANZSRC code: 110306, Endocrinology, 70% ANZSRC code: 110602, Exercise Physiology, 30% Fields of Research (FoR) Classification FoR code: 1103 Clinical Sciences, 70% FoR code: 1106, Human Movement and Sports Science, 30% Abbreviations used in the thesis ADP adenosine diphosphate AES anaerobic energy system ANOVA analysis of variance ATP adenosine triphosphate B2M beta 2 microglobulin BMI body mass index CT computerized tomography CTP I carnitine palmitoyl transferase I CYR61 cysteine-rich, angiogenic inducer 61 DXA dual energy x-ray absorptiometry DUSP1 dual specificity phosphatase 1 EGR1 early growth response 1 FA fatty acid FABP-3 fatty acid binding protein-3 FASN fatty acid synthase FOS FBJ murine osteosarcoma viral oncogene homolog G0S2 G0/G1 switch 2 GH growth hormone GHD growth hormone deficiency HMGCS2 3-hydroxy-3-methylglutaryl-CoA synthase 2 IGFI insulin like growth factor I IL32 interleukin 32 LBM lean body mass MT2A metallothionein 2A LDH lactate dehydrogenase 10 MHC myosin heavy chain MRI magnetic resonance
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