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Calorie Restriction and the Aging Muscle: a Multispecies Approach

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Calorie Restriction and the Aging Muscle: a Multispecies Approach CALORIE RESTRICTION AND THE AGING MUSCLE: A MULTISPECIES APPROACH Melissa C. Orenduff A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition in the Gillings School of Global Public Health. Chapel Hill 2020 Approved by: Stephen D. Hursting Melinda A. Beck Saame Raza Shaikh Kim M. Huffman Jane F. Pendergast © 2020 Melissa C. Orenduff ALL RIGHTS RESERVED ii ABSTRACT Melissa C. Orenduff: Calorie Restriction and the Aging Muscle: A Multispecies Approach (Under the direction of Stephen D. Hursting) Aging is associated with a progressive decline in muscle mass, strength, and physical function termed sarcopenia. Sarcopenia is an important risk factor for loss of independence, reduced quality of life, and increased mortality. Calorie restriction (CR) is an effective dietary treatment for several age-related conditions, including sarcopenia. Recent work conducted in our laboratory suggests insulin-like growth factor-1 (IGF-1) is involved in the anti-aging effects of CR. The aim of this work is to understand the role of circulating IGF-1 in CR-induced effects on aging skeletal muscle. Using a multispecies approach, we sought to determine if IGF-1- mediated effects of CR are conserved among mice, nonhuman primates, and humans. As an extension into our investigation of CR and IGF-1 on aging muscle, we conducted an in vivo experiment to examine the role of a CR mimetic, rapamycin, on age-related loss of muscle strength and function. Our results suggest that the effects of CR on aging skeletal muscle are realized through biological changes consistent with regenerative and repair-related mechanisms and a shift in transcriptional profiles towards improved metabolic and inflammatory signaling pathways that promote enhanced mitochondrial function and biogenesis. Collectively, this work demonstrates CR-induced effects on aging muscle are, in part, supported by reduced circulating IGF-1. Further, the CR-mimetic, rapamycin may hold promise as a pharmacological alternative to CR to attenuate loss of muscle strength and function associated with age. iii To my fiancé, Carl, my Children, Morgan and Garrett, and extended family, thank you for the encouragement, support, and love throughout this journey. iv TABLE OF CONTENTS LIST OF TABLES .................................................................................................................. viii LIST OF FIGURES .................................................................................................................. ix LIST OF ABBREVIATIONS..................................................................................................... x THESIS PRELUDE ................................................................................................................... 1 CHAPTER I: OVERVIEW AND SPECIFIC AIMS ................................................................... 3 Overview ........................................................................................................................ 3 Specific Aims ................................................................................................................. 6 CHAPTER II: BACKGROUND AND SIGNFICANCE............................................................. 9 Impact of age-related changes on skeletal muscle architecture and metabolism .............................................................................................................. 9 The calorie restriction paradigm: Dietary modulation of aging ......................................10 Rodent CR studies..............................................................................................11 Nonhuman primate CR studies ...........................................................................11 Human CR study ................................................................................................12 Calorie restriction (CR) mitigates sarcopenia in various mammalian species..................13 CR-induced effects on age-related loss in mice ..................................................14 CR-induced effects on age-related loss in nonhuman primates ...........................15 CR-induced effects on age-related muscle loss in humans ..................................15 Summary of CR-induced effects on age-related loss in multiple species..................................................................................................16 v Role of IGF signaling in skeletal muscle growth, maintenance, and repair, a process that involves stimulating anabolic pathways and suppressing catabolic activity ..................................................................................17 Supporting roles of IGFBPs in CR-induced effects to mitigate Sarcopenia .....................................................................................................................18 Effect of the CR mimetic, Rapamycin on biological aging .............................................19 CHAPTER III: THE IMPACT OF CALORIE RESTRICTION OR RAPAMYCIN ON AGE- AND SARCOPENIA-ASSOCIATED TRANSCRIPTIONAL SIGNITURES IN SKELETAL MUSCLE .............................................23 Introduction ...................................................................................................................23 Materials and Methods ..................................................................................................26 Calorie restrction on transcriptional signatures in skeletal muscle.......................26 Effects of CR versus Rapamycin on Transcriptional signatures in skeletal muscle ...................................................................................................28 Results ...........................................................................................................................34 CR induces changes in skeletal muscle mass of mice and humans ......................34 Gene expression analysis reveals metabolic networks are engaged by CR in skeletal muscle of mice and humans ......................................35 Influence of CR and Rapamycin on age-related loss of muscle mass, strength, and function ...................................................................39 Effects of rapamycin and CR on gene expression in skeletal muscle ...................41 Discussion .....................................................................................................................44 CHAPTER IV: MECHANISTIC ROLE OF RECUDED CIRCULATING LEVELS OF FREE IGF-1 INDUCED BY CALORIE RESTRICTION ON AGE-RELATED MUSCLE LOSS .....................................................................................84 Introduction ...................................................................................................................84 Materials and Methods ..................................................................................................87 Results ...........................................................................................................................90 vi Discussion .....................................................................................................................92 CHAPTER V: SYNTHESIS ................................................................................................... 100 Overview of research findings ..................................................................................... 100 Public health mplications and future perspectives ........................................................ 102 APPENDIX 1: EFFECT OF CALORIE RESTRICTION ON SYSTEMIC BIOMARKERS OF THE IGF SYSTEM IN MICE, NONHUMAN PRIMATES, AND HUMANS...................................................................................................................... 106 APPENDIX 2: ASSOCIATIONS BETWEEN INSULIN-LIKE GROWTH FACTOR (IGF) BINDING PROTEIN-7 AND SOCIO-DEMOGRAPHIC VARIABLES, BODY MASS INDEX, AND ALL-CAUSE MORTALITY IN POSTMENOPAUSAL WOMEN FROM THE WOMEN'S HEALTH INITIATIVE OBSERVATION STUDY....................................................................................................... 116 REFERENCES ....................................................................................................................... 136 vii LIST OF TABLES Table 2.1: Hallmark and BioCarta gene set enrichment in quadriceps muscle from CR versus control mice .............................................................................22 Table 3.1: Gene set enrichment analysis at 12 months ..............................................................58 Table 3.2: Gene set enrichment analysis at 24 months ..............................................................59 Table 3.3: Gene list for Reactome and KEGG gene sets commonly enriched in mice and humans .......................................................................................................60 Table 3.4: Gene Set Enrichment (Hallmark) for male mice .......................................................72 Table 3.5: Gene Set Enrichment (Hallmark) for female mice ....................................................72 Table 3.6: Gene Set Enrichment (Hallmark) for male and female mice in rapamycin group .............................................................................................. 72 Supplemental Table 3.1S. Gene set enrichment analysis for mouse samples .............................73 Supplemental Table 3.2S. Gene set enrichment analysis for human
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