RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta tese será disponibilizado somente a partir de 05/05/2025. SAO PAULO STATE UNIVERSITY “JÚLIO DE MESQUITA FILHO” SCHOOL OF MEDICINE Julí Thomaz de Souza Influence of protein and creatine supplementation on functional capacity, quality of life and muscle function after stroke Thesis presented to the School of Medicine, Sao Paulo State University “Júlio de Mesquita Filho”, Campus Botucatu, to obtain the title of Ph.D. in Pathophysiology in Internal Medicine Advisor: Professor Paula Schmidt Azevedo Gaiolla Co-advisor: Professor Rodrigo Bazan Botucatu 2023 Julí Thomaz de Souza Influence of protein and creatine supplementation on functional capacity, quality of life and muscle function after stroke Thesis presented to the School of Medicine, Sao Paulo State University “Júlio de Mesquita Filho”, Campus Botucatu, to obtain the title of Ph.D. in Pathophysiology in Internal Medicine. Advisor: Professor Paula Schmidt Azevedo Gaiolla Co-advisor: Professor Rodrigo Bazan Botucatu 2023 Dedication To my parents, Luiz and Fernanda, who always encouraged me and gave me all the support I needed to have the opportunity to follow my dreams. To my sister Camila, who, in addition to being a sister, is my friend and has always been by my side in all important moments. To my nieces Serena and Videl, who are everything to me. To my husband, Luiz Vieira, for all his patience, love, and dedication during all these years of partnership. To Edgar, our furry pet, who is our greatest joy. To my stepmother Cristina, my husband's family, Vânia, Dhiogo, Aline, Luísa, and all my family and dear friends who have always encouraged and supported me in all my missions. To patients and their families who, even in their moment of greatest pain and suffering, were sensitive enough to contribute to the advancement of science by helping those who research to improve the quality of life of the collective. Nothing would be possible without you. Special acknowledgments To my advisor, Professor Paula Schmidt Azevedo Gaiolla, for all the shared knowledge, encouragement, and confidence in my work. Thank you for always being this example of a researcher, professor, and strong and determined woman. Thank you for everything. To my co-advisor, Professor Rodrigo Bazan, for always being a great encourager and booster of my career. To my dear professor Sérgio Alberto Rupp de Paiva, for his generosity and humility in always helping me when I look for him with doubts. The greatest example for all of us and I will be forever grateful for the opportunity to learn from you. To Professor Marcos Ferreira Minicucci, for all the partnership and teachings during all these years, to Professors Leonardo Mamede Zornoff, Silméia Garcia Zanati Bazan, Bertha Furlan Polegato, Filipe Welson and Suzana Érico Tanni for the immense contribution for this work to have been developed with quality. I am eternally grateful for all the learning. To my dear friend, nurse Natália Ferreira, who was always by my side throughout the process, making an important contribution to this work. Thank you for your professionalism and friendship. To all the professionals of the Stroke Unit, especially the nurse Bruna Pegorer and the nursing technicians Maria Izabel, Geovana, Andréia, Paulinho, and Evany for always contributing to data collection. Thank you for your help, partnership, and professionalism, who daily assist our patients and their families with so much love, good humor, and care. To my friends and colleagues Lívia Santos, Fernanda, Luana, and Ana for all the encouragement, support, partnership, and friendship. To my friend and English teacher, Anita. For all the friendship, teaching, help, and encouragement. Acknowledgments To the professors of the main committee, Prof. Paula Schmidt Azevedo Gaiolla, Prof. Adam Lee Gordon, Prof. Marcos Ferreira Minicucci, Prof. Gustavo José Luvizutto, and Prof. Ivan Aprahamian, and to the alternate professors, Prof. Suzana Erico Tanni, Prof. Ruth Caldeira de Melo, Prof. Bruna Paola Murino Rafacho for their great availability and contribution. To the medical residents of neurology and internal medicine and colleagues of the multi- professional residency for all their support, teachings, patience, and help during data collection. To the neurologists Daniel, Vinícius, Robson, Gabriel, and everyone who facilitated data collection during the research. To the colleague nutritionist Maria Fernanda Fernandes, who made an important contribution to data collection as a scientific initiation student. To the entire UNIPEX team for helping with the storage of biological material. To the entire UPECLIN, EAP, CEP, and DGAA team for their help with documentation and bureaucratic matters. To the entire team at the library, Departments of Internal Medicine and Neurology for all the assistance provided during the development of this project. To Vânia, Bruna, and all the employees of the Graduate Section. To the entire team at the University of Nottingham who gave me a wonderful welcome at the Royal Derby Hospital during my internship in Derby, UK. In particular, professors Kenneth Smith, Daniel Wilkinson, and Adam Gordon. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The study is financed by the National Council for Scientific and Technological Development (CNPq) (435047/2018-3) Epigraph “O real não está na saída nem na chegada: ele se dispõe para a gente é no meio da travessia” Grande sertão: Veredas - João Guimarães Rosa “The truth is not in the setting out nor in the arriving: it comes to us in the middle of the journey” The Devil to Pay in the Backlands - João Guimarães Rosa https://en.wikipedia.org/wiki/The_Devil_to_Pay_in_the_Backlands https://en.wikipedia.org/wiki/The_Devil_to_Pay_in_the_Backlands RESUMO Introdução: O AVC é uma das principais causas de mortalidade e incapacidade. A fase aguda do AVC é marcada por inflamação, inapetência, disfagia, repouso no leito e alterações da mobilidade que podem comprometer o estado nutricional. Este estudo teve como objetivo avaliar o efeito da suplementação de creatina na massa muscular, força e capacidade funcional de idosos com AVC. Além disso, foram avaliados marcadores bioquímicos de inflamação, degradação muscular e síntese. Metodologia: Ensaio clínico randomizado, duplo-cego, com idosos na fase aguda do AVC. Os participantes foram divididos em dois grupos: Tratamento (recebeu 10g de creatina 2x/dia) e Controle (recebeu 10g de placebo 2x/dia). Ambos os grupos receberam suplementação com proteína isolada do soro do leite em pó para atingir a meta de 1,5g de proteína/kg de peso corporal/dia e atendimento de fisioterapia diário. A intervenção ocorreu em 7 dias de internação. Verificou-se a influência da creatina na massa muscular (bioimpedância e ultrassonografia muscular), força (preensão manual e National Institutes of Health Stroke Scale), capacidade funcional (Escala de Rankin modificada), marcadores bioquímicos (3-Metil- histidina, Interleucina-6, Fator de crescimento semelhante à insulina tipo 1, fator de crescimento/diferenciação-15, procolágeno tipo III, insulina e progranulina). Acompanhamento para verificar capacidade funcional, força muscular, mortalidade e qualidade de vida 90 dias após o AVC. Resultados: Trinta idosos foram incluídos em 2 grupos homogêneos, a maioria do sexo masculino com AVC isquêmico moderado. A suplementação de creatina não influenciou o peso corporal, força muscular, capacidade funcional e massa muscular avaliada por ultrassom e bioimpedância. No entanto, houve um aumento no índice de massa muscular apendicular em homens, mas não em mulheres. Não houve diferença estatisticamente significativa em relação ao uso de creatina e níveis séricos de IL-6 e IGF-1, bem como procolágeno Tipo III, insulina, GDF-15 e 3-Metil-histidina. A creatina influenciou na diminuição da progranulina. A oferta calórica de 21-25 kcal/kg com 1,5g de proteína/kg por dia mostrou-se adequada para a manutenção do peso independentemente da administração de creatina. A creatina não influenciou a mortalidade e a percepção de qualidade de vida 90 dias após o AVC. Discussão: A suplementação foi segura com poucos eventos adversos relacionados e boa tolerância e aceitação. Houve um aumento no índice de massa muscular apendicular em homens, mas não em mulheres. Esse aumento agudo da massa muscular pode ser devido ao edema muscular, uma vez que o transporte de creatina para dentro da célula depende do sódio. De fato, a resposta muscular à creatina é diferente em homens e mulheres. Observa-se que há potencial para a creatina modular alguns aspectos relacionados a biomarcadores inflamatórios no AVC agudo. A literatura mostra a associação entre aumento da progranulina e mortalidade e pior prognóstico funcional após o AVC. Em nossos achados, no grupo tratamento, observou-se redução da progranulina, mas não no grupo controle. Este resultado representa o papel anti-inflamatório da creatina. Assim, a novidade deste estudo é mostrar o potencial da creatina em modular a progranulina na fase aguda do AVC. O trabalho trouxe dados essenciais relacionados à ingestão calórico-proteica durante a internação, mostrando a importância da adequação nutricional para evitar a perda de peso nesse período. Conclusão: A suplementação de creatina provou ser segura. Tem o potencial de modular alguns marcadores inflamatórios após o AVC e influenciou na redução dos valores de progranulina, refletindo seu papel anti-inflamatório. A creatina não afetou a capacidade funcional e a força, mas aumentou a massa muscular apendicular em homens. Estudos com maior número de participantes e maior tempo de intervenção devem ser realizados para melhor compreender a influência da suplementação de creatina na fase aguda do AVC. Palavras-chave: Acidente vascular cerebral; Creatina; Músculo esquelético. ABSTRACT Background: Stroke is a leading cause of mortality and disability. The acute phase of stroke is marked by inflammation, loss of appetite, dysphagia, bed rest, and mobility changes that can compromise the nutritional status. This study aimed to evaluate the effect of creatine supplementation on muscle mass, strength, and functional capacity of older people with stroke. In addition, biochemical markers of inflammation, muscle degradation, and synthesis were assessed. Methodology: Randomized, double-blind, clinical trial with older people in the acute phase of stroke. The participants were divided into two groups: Treatment (received 10g of creatine 2x/day) and Control (received 10g of placebo 2x/day). Both groups received supplementation with powdered milk protein serum isolate to achieve the goal of 1.5g of protein/kg of body weight/day and daily early mobility training. The intervention occurred in 7-days hospitalization. Were verified the influence of creatine on muscle mass (bioimpedance and muscle ultrasound), strength (handgrip and National Institutes of Health Stroke Scale), functional capacity (Modified Rankin Scale), biochemical markers (3-Methylhistidine, Interleukin-6, Insulin-like growth factor 1, Growth/Differentiation Factor-15, type III procollagen, insulin, and progranulin). Follow-up to verify functional capacity, muscle strength, mortality, and quality of life 90 days after stroke. Results: Thirty older people were included in 2 homogeneous groups, mostly male with moderate ischemic stroke. Creatine supplementation did not influence body weight, muscle strength, functional capacity, and muscle mass evaluated by ultrasound and bioimpedance. However, there was an increase in appendicular muscle mass index in men but not in women. There was no statistically significant difference regarding the use of creatine and serum levels of IL-6 and IGF-1, as also Type III procollagen, insulin, GDF-15, and 3-Methylhistidine. Creatine influenced the decrease of progranulin. The caloric supply of 21-25 kcal/kg with 1.5g of protein/kg per day proved adequate for weight maintenance regardless of creatine administration. Creatine did not influence mortality and perception of quality of life 90 days after stroke. Discussion: Supplementation was safe with few related adverse events and good tolerance and acceptance. There was an increase in appendicular muscle mass index in men but not in women. This acute increase in muscle mass may be due to muscle edema since creatine transport into the cell depends on sodium. Indeed, the muscular response to creatine is different in men and women. It is observed that there is potential for creatine to modulate some aspects related to inflammatory biomarkers in acute stroke. Literature shows the association between increased progranulin and mortality and worse functional prognosis after stroke. In our findings, in the treatment group, the reduction in progranulin was observed, but not in the control group. This result represents the anti-inflammatory role of creatine. Thus, the novelty of this study is to show the potential of creatine to modulate progranulin in the acute phase of the stroke. The work brought essential data related to caloric-protein intake during hospitalization, showing the importance of nutritional adjustment to avoid weight loss during this period. Conclusion: Creatine supplementation proved to be safe. It has the potential to modulate some inflammatory markers after stroke and influenced the reduction of progranulin values, reflecting its anti-inflammatory role. Creatine did not impact functional capacity, and strength but increased appendicular muscle mass in men. Studies with a larger number of participants and longer intervention time should be carried out to better understand the influence of creatine supplementation in the acute phase of stroke. Keywords: Stroke; Creatine; Skeletal Muscle. LIST OF ILUSTRATIONS Figure 1 Flow diagram of the ICaRUS Stroke Trial ............................................................................ 27 Figure 2 ICaRUS Stroke Trial template of recommended content for the schedule of screening, interventions, and assessments ......................................................................................... 32 Figure 3 Flowchart of inclusion of participants in the ICaRUS Stroke Trial from July/2019 to November/2022 ............................................................................................................... 46 Figure 4 Adverse events that occurred during participation of older people in the ICaRUS Stroke Trial .................................................................................................................................... 49 Figure 5 Body composition variables of older people who participated in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo ............................................................................................................................. 55 Figure 6 Appendicular muscle mass index of older during participation in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo corrected by sex ................................................................................................... 56 Figure 7 Muscle strength variables of older people during participation in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo ............................................................................................................................. 58 Figure 8 Functional capacity by Modified Rankin Scale of older people who participated in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo .............................................................................................. 59 Figure 9 Biochemical markers of older people who participated in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo .............................................................................................................................. 61 Figure 10 3MH biomarker by labeled isotope of older people who participated in the ICaRUS Stroke Trial in the first 24 hours after stroke and on the 7th day of intervention with creatine versus placebo corrected by sex .......................................................................... 62 Figure 11 Kaplan-Meier survival curve of the older people during participation in the Icarus Stroke Trial .................................................................................................................................... 63 LIST OF TABLES Table 1 Comparison between treatment and control groups of the general characteristics of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at baseline visit .............................................................. 47 Table 2 Comparison between treatment and control groups of the neurological characteristics of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at baseline visit .............................................................. 48 Table 3 Comparison between treatment and control groups of the body composition of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at baseline visit .................................................................................... 50 Table 4 Comparison between treatment and control groups of the muscle strength of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at baseline visit .................................................................................... 51 Table 5 Comparison between treatment and control groups of the biochemical exams and bio markers of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at baseline visit .......................................... 52 Table 6 Evaluation of the influence of creatine treatment on muscle mass in older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial .................................................................................................. 54 Table 7 Evaluation of the influence of creatine treatment on appendicular muscle mass index of older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial corrected by sex .................................... 56 Table 8 Evaluation of the influence of creatine treatment on muscle strength in older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial .................................................................... 57 Table 9 Evaluation of the influence of creatine treatment on functional capacity in older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial .................................................................... 59 Table 10 Evaluation of the influence of creatine treatment on biochemical markers of older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial ........................................................................ 60 Table 11 Evaluation of the influence of creatine treatment on the 3MH biomarker by labeled isotope of older people hospitalized for stroke after seven days of supplementation during participation in the Icarus Stroke Trial corrected by sex ........................................ 62 Table 12 Comparison between treatment and control groups on the perception of quality of life, anxiety, and depression of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at the follow-up visit .................................... 64 Table 13 Comparison between treatment and control groups of results from 7-day food record of older people with ischemic stroke during the participation in the ICaRUS Stroke Trial ................................................................................................................. 65 Table 14 Comparison between treatment and control groups of results from 24-hour Dietary Recall of older people hospitalized for ischemic stroke who participated in the ICaRUS Stroke Trial at the follow-up visit ................................................................... 65 Table 15 Consumption of food groups by older people with ischemic stroke who participated in the ICaRUS Stroke Trial ........................................................................................... 66 LIST OF ABBREVIATIONS AND ACRONYMS AC: Arm circumference AMA: Arm muscle area AMMI: Appendicular muscle mass index APMT: Adductor pollicis muscle thickness ASPECTS: Alberta Stroke Program Early CT Score BBM: Biceps brachii muscle BMI: Body mass index CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration cm: Centimeter ECW: Extracellular water ELISA: Enzyme-Linked Immunosorbent Assay ET: End of treatment EuroQol-5D: The European Quality of life Scale Five Dimension FAS: Full Analysis Set FFMI: Fat free mass index FFQ: Food Frequency Questionnaire FOIS: Functional Oral Intake Scale g: Grams GDF-15: Growth/Differentiation Factor-15 h: Hour HADS: Hospital Anxiety and Depression Scale HbA1C: Hemoglobin A1C HDL: High-density lipoprotein HOMA-IR: Homeostasis assessment model of insulin resistance ICaRUS: Influence of protein and Creatine supplementation on functional capacity, quality of life and mUScle function after Stroke IGF-1: Insulin-like growth factor 1 IL-6: Interleukin-6 kg: Kilograms kgf: Kilogram-force kHz: Kilohertz l: Liters LACS: Lacunar syndrome LDL: Low-density lipoprotein m: Meter 3MH: 3-Methylhistidine MHz: Megahertz min: Minute ml: Milliliter mm: millimeter MPB: Muscle protein breakdown MPS: Muscle protein synthesis mRs: Modified Rankin Scale N: Number NIHSS: National Institutes of Health Stroke Scale NRS: Nutritional risk screening P3NP: Type III procollagen N-terminal peptide PACS: Partial anterior circulation syndrome PL: Placebo POCS: Posterior circulation syndrome PP: Per-Protocol RFM: Rectus femoris muscle rpm: Revolutions per minute SMM: Skeletal muscle mass ST: Start of treatment TACS: Total anterior circulation syndrome TBW: Total body water TNF- α: Tumour necrosis factor α TOAST: Trial of Org 10172 in Acute Stroke Treatment TR: Treatment TST: Triceps skinfold thickness US: Ultrasound SUMMARY 1 INTRODUCTION ....................................................................................................... 20 1.1 Stroke ..................................................................................................................... 20 1.2 Stroke and nutritional conditions ........................................................................... 21 1.3 Biomarkers of inflammation, muscle breakdown and protein synthesis ................... 22 1.4 Protein and creatine supplementation .................................................................... 23 2 HYPOTHESIS ............................................................................................................ 25 3 AIMS ....................................................................................................................... 25 4 METHODOLOGY ...................................................................................................... 26 4.1 Trial design .......................................................................................................... 26 4.2 Participants and eligibility criteria ........................................................................ 28 4.3 Interventions ...................................................................................................... 28 4.4 Outcomes ............................................................................................................ 30 4.5 Procedures ........................................................................................................... 30 4.6 Randomization ..................................................................................................... 33 4.7 Blinding ................................................................................................................ 33 4.8 Security and data management ............................................................................ 33 4.9 Protocol assessment ............................................................................................ 34 4.9.1 Clinical assessment .................................................................................................. 34 4.9.2 Nutritional assessment ............................................................................................ 35 4.9.3 Body composition assessment ................................................................................ 36 4.9.4 Muscle strength assessment ................................................................................... 37 4.9.5 Functional capacity assessment .............................................................................. 38 4.9.6 Dependence degree assessment ............................................................................. 38 4.9.7 Blood collection and biochemical dosages .............................................................. 38 4.9.8 Assessment of anxiety and depression ................................................................... 41 4.9.9 Quality of life assessment ....................................................................................... 41 4.9.10 Assessment of eating habits .................................................................................. 41 4.10 Statistical analysis .............................................................................................. 42 4.11 Data monitoring ................................................................................................. 43 4.12 Ethics approval and consent to participate ......................................................... 44 5 RESULTS .................................................................................................................. 45 6 DISCUSSION ............................................................................................................ 67 7 CONCLUSION .......................................................................................................... 74 REFERENCES .............................................................................................................. 75 APPENDIX A - INFORMED CONSENT FORM .............................................................. 87 APPENDIX B - RESULTS OF MUSCLE STRENGHT AND FUNCTION AFTER 90 DAYS ...... 90 ANNEX A - APPROVAL DOCUMENT OF RESEARCH ETHICS COMMITTEE FROM BOTUCATU MEDICAL SCHOOL .................................................................................. 91 ANNEX B - APPROVAL DOCUMENT OF RESEARCH ETHICS COMMITTEE FROM BOTUCATU MEDICAL SCHOOL - AMENDMENT 1 ....................................................... 95 ANNEX C - APPROVAL DOCUMENT OF RESEARCH ETHICS COMMITTEE FROM BOTUCATU MEDICAL SCHOOL - AMENDMENT 2 ....................................................... 100 74 in the acute phase of stroke and its reduction with the use of creatine need to be explored in future studies, as this is a site of therapeutic potential. 7 CONCLUSION Creatine supplementation proved to be safe, with good tolerance and easy acceptance. Creatine did not impact functional capacity, and strength but increased appendicular muscle mass in men. It has the potential to modulate some inflammatory markers after stroke and had an influence on the reduction of progranulin values, reflecting its anti-inflammatory role. Supplementation had no impact on mortality and quality of life after the event. This study helped to understand the potencial role and safe of creatine in the acute phase of the stroke, which supports the development of other trials. In fact, studies with larger number of participants and longer intervention time should be carried out to better understand the influence of creatine supplementation in the acute phase of stroke. 75 REFERENCES 1. Ministério da Saúde (BR). Secretaria de Atenção à Saúde. Departamento de Ações Programáticas Estratégicas. Diretrizes de atenção à reabilitação da pessoa com acidente vascular cerebral. 2013. 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