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Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle

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Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle Torque Loss in a Mouse Model of Duchenne Muscular Dystrophy Justin E. Sperringer Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the Doctor of Philosophy in Human Nutrition, Foods, & Exercise Advisory Committee: Committee Chair – Susan Hutson Committee Co-Chair – Matthew Hulver Robert Grange Dongmin Liu Samer El-Kadi August 2nd, 2019 Blacksburg, VA Keywords: Duchenne Muscular Dystrophy; dystrophin; dystrophin glycoprotein complex; amino acids; branched-chain amino acids; leucine; isoleucine; valine; mTOR; skeletal muscle; muscle function Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle Torque Loss in a Mouse Model of Duchenne Muscular Dystrophy Justin E. Sperringer Academic Abstract Duchenne Muscular Dystrophy (DMD) is an X-linked recessive, progressive muscle-wasting disease characterized by mutations in the dystrophin gene. Duchenne muscular dystrophy is the most common and most severe form of inherited muscle diseases, with an incidence of 1 in 3,500 male births1,2. Mutations in the dystrophin gene result in non-functional dystrophin or the complete absence of the protein dystrophin, resulting in necrosis and fibrosis in the muscle, loss of ambulation, cardiomyopathies, inadequate or failure of respiratory function, and decreased lifespan. Although there has been little research for effective nutritional strategies, dietary intervention may be effective as an adjuvant treatment. In this study, wild type (WT) and mdx animals were provided either a control or elevated branched chain amino acid (BCAA) diet nocturnally for 25 weeks to determine if the elevated BCAAs would attenuate muscle torque loss. Twenty-five weeks of chronic, elevated BCAA supplementation had no impact on muscle function measures. Interestingly, mdx and WT animals had the same torque responses in the low stimulation frequencies (1 Hz – 30 Hz) compared to higher stimulation frequencies. Tetanus was reached at a much lower stimulation frequency in mdx animals compared to WT animals (100 Hz vs +150 Hz). The mdx mouse consistently had more cage activity in the light cycle X- and Y-planes. Interestingly, animals on the BCAA diet increased X-, Y-, and Z-plane activity in the dark cycles at four weeks while animals on the control diet more Z-plane activity at 25 weeks, although not significant. All three BCAAs were elevated in the plasma at 25 weeks, although only Leu was significantly elevated. The BCAAs had no effect on. The diaphragm and skeletal muscle masses were larger in mdx animals, and WT animals had a significantly larger epididymal fat pad. The active state of BCKDC determined by phosphorylation of the E1α enzyme was greater in WT animals in white skeletal muscle, but not red skeletal muscle. Protein synthesis effectors of the mTORC1 signaling pathway and autophagy markers were similar among groups. Wild type animals had increased mTORC1 effectors and animals on the BCAA diet had decreased autophagy markers, although not significant. Although BCAAs did not affect muscle function, fibrosis, or protein synthesis effectors, this study illustrates the functionality of mdx muscles over time. It would be interesting to see how the different muscle fiber types are affected by DMD, noting the differences between the diaphragm, heart, red muscle, and white muscle fibrosis markers. Although there was no increase in mTORC1 effectors with an elevated BCAA diet, it would be interesting to determine muscle protein synthesis, myofibrillar protein synthesis, and total protein turnover in the mdx mouse with an elevated BCAA diet, although the dietary intervention started when mice arrived at 4 weeks of age, earlier intervention may be beneficial early in the disease process. Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle Torque Loss in a Mouse Model of Duchenne Muscular Dystrophy Justin E. Sperringer General Audience Abstract Duchenne Muscular Dystrophy (DMD) is an X-linked recessive, progressive muscle-wasting disease characterized by mutations in the dystrophin gene. Duchenne muscular dystrophy is the most common and most severe form of inherited muscle diseases, with an incidence of 1 in 3,500 male births1,2. Mutations in the dystrophin gene result in non-functional dystrophin or the complete absence of the protein dystrophin, resulting in necrosis and fibrosis in the muscle, loss of movement and walking ability, cardiomyopathies, inadequate or failure of respiratory function, and decreased lifespan. Although there has been little research for effective nutritional strategies, dietary intervention may be effective as an adjuvant treatment and palliative care. The branched chain amino acids (BCAAs) are known to directly stimulate muscle protein synthesis by direct activation of the mechanistic target of rapamycin complex 1 (mTORC1). This study aimed to illustrate the differences between diseased and healthy mice and determine if BCAAs can reduce muscle torque loss. Twenty-five weeks of chronic, elevated BCAA supplementation had no impact on muscle function measures. Interestingly, mdx and WT animals had the same torque responses in the low stimulation frequencies (1 Hz – 30 Hz) compared to higher stimulation frequencies. Tetanus was reached at a much lower stimulation frequency in mdx animals compared to WT animals (100 Hz vs +150 Hz). The mdx mouse consistently had more cage activity in the light cycle X- and Y-planes. Interestingly, animals on the BCAA diet increased X-, Y-, and Z-plane activity in the dark cycles at four weeks while animals on the control diet more Z-plane activity at 25 weeks, although not significant. All three BCAAs were elevated in the plasma at 25 weeks, although only Leu was significantly elevated. The BCAAs had no effect on. The diaphragm and skeletal muscle masses were larger in mdx animals, and WT animals had a significantly larger epididymal fat pad. The active state of BCKDC determined by phosphorylation of the E1α enzyme was greater in WT animals in white skeletal muscle, but not red skeletal muscle. Protein synthesis effectors of the mTORC1 signaling pathway and autophagy markers were similar among groups. Wild type animals had increased mTORC1 effectors and animals on the BCAA diet had decreased autophagy markers, although not significant. Although BCAAs did not affect muscle function, fibrosis, or protein synthesis effectors, this study illustrates the functionality of mdx muscles over time. It would be interesting to see how the different muscle fiber types are affected by DMD, noting the differences between the diaphragm, heart, red muscle, and white muscle fibrosis markers. Although there was no increase in mTORC1 effectors with an elevated BCAA diet, it would be interesting to determine muscle protein synthesis, myofibrillar protein synthesis, and total protein turnover in the mdx mouse with an elevated BCAA diet, although the dietary intervention started when mice arrived at 4 weeks of age, earlier intervention may be beneficial early in the disease process. Table of Contents Academic abstract…………………………………………………………………….………………….. i General audience abstract……………………………………………..……….……………………….. iii Table of contents…………………………………………………………….………………………....… v Dedication………………………………………………………………………….………………...... viii List of abbreviations………………………………………………………………..………….……..… ix List of figures……………………………………………….………………………………...…….…. xiii CHAPTER ONE Introduction………………………………………………………………………………….… 1 Hypotheses…………………………………………………………………………………….. 2 CHAPTER TWO Literature review…………………………………………………………………....................... 3 Clinical description…………………………………………………….……………………….. 3 Diagnosis………………………………………………………………………………………... 3 Dystrophin…………………………………………………………..…………………………... 4 Dystrophin glycoprotein complex……………………………………………..………………... 8 Utrophin……………………………………………………………………………..…. 8 Dystrophin-dystroglycan subcomplex………………….……………………………… 9 Sarcoglycan-sarcospan subcomplex……………………………..……………………... 9 Dystrophin-syntrophin subcomplex………………………………………………….… 9 Signaling associated with the dystrophin glycoprotein complex……………………………..... 10 vi Molecular mechanism of Duchenne muscular dystrophy……………………………………… 12 Myopathies associated with the dystrophin glycoprotein complex…………………………..… 12 Current treatments………………………………………………………………………..……. 15 Pharmacological treatments………………………………………………………...… 18 Genetic strategies……………………………………………………………………... 20 Cellular strategies…………………………………………………………………….. 22 Genome editing……………………………………………………………………….. 22 Nutritional strategies to promote muscle protein synthesis………………………….… 24 mTORC1……………………………………………………………………………………..... 27 Nutritional strategies as an adjuvant therapy………………………………………………..… 28 CHAPTER THREE Chronic Dietary Supplementation of Branched-Chain Amino Acids Does Not Attenuate Muscle Function and Strength Loss in a Mouse Model of Duchenne Muscular Dystrophy……………………………... 30 Methods………………………………………………………………………………………... 30 Animals……………………………………………………………………………….. 30 Diets…………………………………………………………………………………... 30 Body composition…………………………………………………………………….. 33 Metabolic & activity monitoring……………………………..……………………..… 33 in vivo muscle function………………………………………….…………………….. 34 Western blots………………………………………………………………………..… 34 Plasma and tissue amino acids………………………………………………………... 36 Hydroxyproline……………………………………………………….…………….… 37 Statistics……………………………………………………………………………....
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