Muscle power as countermeasure of functional ability decline during aging: age trajectories, assessment, training and application in the clinical setting

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(1)International PhD Thesis. Muscle power as a countermeasure of functional ability decline during aging Age trajectories, assessment, training and application in the clinical setting. Programa de Doctorado en Investigación Sociosanitaria y de la Actividad Física. Julián Alcázar Caminero Toledo, 2019.

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(5) A mis padres, Rosario y Julián, por el apoyo incondicional y por ser la inspiración y el espejo donde mirarme, esta tesis es el fruto de su trabajo.. A mis hermanas, a María Rosa por cuidarme toda mi vida y compartir conmigo sus dos mayores alegrías, y a María Jesús por ser mi ángel de la guarda.. A Cristina, por ser mi equilibrio y complemento perfecto, por sacar lo mejor de mí, y por enseñarme a luchar en los momentos más difíciles..

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(7) International PhD Thesis. Muscle power as a countermeasure of functional ability decline during aging Age trajectories, assessment, training and application in the clinical setting. Julián Alcázar Caminero. Supervisors Luis M. Alegre Durán and Amelia Guadalupe Grau Tutor Ignacio Ara Royo. Universidad de Castilla-La Mancha Programa de Doctorado de Investigación Sociosanitaria y de la Actividad Física Departamento de Actividad Física y Ciencias del Deporte Facultad de Ciencias del Deporte. Toledo, Spain (2019).

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(15) TABLE OF CONTENTS Grants and sources of funding ………………………………………. 18. List of scientific contributions ……………………………………….. 20. Research stays …………………………………………………………. 25. Abstract ………………………………………………………………... 26. List of tables ………………………………………………………….... 31. List of figures ………………………………………………………….. 36. List of abbreviations …………………………………………………... 41. 1. INTRODUCTION AND JUSTIFICATION ……………………. 45. 1.1 The population aging in numbers ……………………………... 46. 1.2 Towards a more disabled older population …………………... 48. 1.3 Functional ability as the core component of healthy aging …. 50. 1.4 The impact of skeletal muscle structure and function in functional ability ……………………………………………………. 53. 1.4.1 Sarcopenia …………………………………………………... 54. 1.4.2 Muscle power ……………………………………………….. 56. 1.5 Assessment of muscle power in older adults …………………. 59. 1.6 Muscle power training in older adults ………………………... 63. 1.7 Muscle power in the clinical setting ………………………….... 65. 1.8 Justification …………………………………………………….... 67. 2. OBJECTIVES AND HYPOTHESES ……………………………... 71. 3. MATERIAL AND METHODS ………..………………………….. 79. 3.1 Systematic review ………………………………………………. 80. 3.1.1 Literature search ……………………………………………. 80. 3.1.2 Inclusion and exclusion criteria ………………………….... 80.

(16) 3.1.3 Coding of studies ………………………………………….... 81. 3.1.4 Risk of bias …………………………………………………... 83. 3.2 Participants of the studies …………………………………….... 84. 3.2.1 The Copenhagen Sarcopenia Study cohort ………………. 84. 3.2.2 Community-dwelling older adults ……………………….. 85. 3.2.3 Older adults with COPD …………………………………... 87. 3.2.4 The Toledo Study for Healthy Aging cohort …………….. 88. 3.2.5 The European cohort ……………………………………….. 90. 3.3 Assessment of anthropometrics and body composition …….. 90. 3.3.1 Anthropometrics ………………………………………….... 90. 3.3.2 Body composition ………………………………………….. 92. 3.3.3 Skeletal muscle mass ………………………………………. 93. 3.4 Assessment of resting peripheral capillary oxygen saturation and lung function ………………………………………. 95. 3.5 Assessment of physical performance, cognitive function, frailty, disability, comorbidity and health-related quality of life ……………………………………………………………………….... 96. 3.6 Assessment of cardiopulmonary exercise capacity ………….. 98. 3.7 Assessment of maximal voluntary isometric contraction ….... 99. 3.7.1 Handgrip strength ………………………………………….. 99. 3.7.2 Bilateral leg extension strength ……………………………. 99. 3.8 Assessment of the force-velocity relationship and muscle power ……………………………………………………………….... 100. 3.8.1 Nottingham power rig ……………………………………... 100. 3.8.2 Instrumented leg press machine …………………………... 101. 3.8.3 The sit-to-stand muscle power test ………………………... 106. 3.9 Assessment of systemic oxidative stress …………………….... 111. 3.10 Exercise training program …………………………………….. 112.

(17) 3.11 Monitoring of adverse events ……………………………….... 113. 3.12 Statistical analysis ……………………………………………... 113. 4. RESULTS ………………………………………………………….... 127. 4.1 Study 1: Lower-limb muscle power throughout the lifespan ……………………………………………………………………….... 128. 4.2 Study 2: Systematic review on muscle power testing ………... 158. 4.3 Study 3: Reliability and validity of force-velocity testing ….... 170. 4.4 Study 4: Force-velocity relationship and stretch-shortening cycle ………………………………………………………………….. 180. 4.5 Study 5: Concurrent training in older people with COPD …... 192. 4.6 Study 6: The 5-rep sit-to-stand power test …………………….. 206. 4.7 Study 7: The 30-s sit-to-stand power test ……………………... 214. 4.8 Study 8: Sit-to-stand power throughout the lifespan ………... 238. 4.9 Study 9: Operational definition of low relative muscle power ……………………………………………………………………….... 264. 4.10 Study 10: Cut-off points for low relative muscle power ……………………………………………………………………….... 294. 5. DISCUSSION …………………………………………………….... 337. 5.1 Study 1: Lower-limb muscle power throughout the lifespan ……………………………………………………………………….... 338. 5.2 Study 2: Systematic review on muscle power testing ………... 348. 5.3 Study 3: Reliability and validity of force-velocity testing ….... 354. 5.4 Study 4: Force-velocity relationship and stretch-shortening cycle ………………………………………………………………….. 361. 5.5 Study 5: Concurrent training in older people with COPD …... 367. 5.6 Study 6: The 5-rep sit-to-stand power test …………………….. 374.

(18) 5.7 Study 7: The 30-s sit-to-stand power test ……………………... 378. 5.8 Study 8: Sit-to-stand power throughout the lifespan ………... 382. 5.9 Study 9: Operational definition of low relative muscle power ……………………………………………………………………….... 389. 5.10 Study 10: Cut-off points for low relative muscle power ……………………………………………………………………….... 397. 6. CONCLUSIONS ………………………………………………….... 405. 7. PERSPECTIVES ……………………………………………………. 413. 8. ACKNOWLEDGEMENTS ……………………………………….. 419. 9. REFERENCES …………………………………………………….... 423. 10. SUPPLEMENTARY MATERIAL ………………………………. 477. 10.1 Supplementary table 1 ………………………………………... 478. 10.2 Supplementary table 2 ……………………………………….... 487. 10.3 Supplementary table 3 ……………………………………….... 494. 11. APPENDIX ………………………………………………………... 497. 11.1 Appendix 1 ……………………………………………………... 498. 11.2 Appendix 2 ……………………………………………………... 500.

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(20) GRANTS AND SOURCES OF FUNDING. GRANTS AND SOURCES OF FUNDING The following funding organizations have directly contributed to the realization of the present PhD Thesis:. Research projects -. The Biomedical Research Networking Center of Frailty and Healthy Aging (CIBERFES) and FEDER funds from the European. Union. (Grant. numbers:. CB16/10/00477,. CB16/10/00456 and CB16/10/00464). -. The Ministerio de Economía y Competitividad of the Government of Spain (MINECO/FEDER, EU) (Grant numbers: DEP2015-69386-R and BES-2016077199).. Scholarships -. Ayudas para contratos predoctorales para la Formación del Profesorado Universitario (FPU), de los subprogramas de Formación y Movilidad dentro del Programa Estatal de Promoción del Talento y su Empleabilidad (Boletín Oficial del Estado, Viernes 28 de Agosto de 2015, Número 206, Sección III, Página 76639). Duration: 48 months. (Grant number: FPU014/05106). -. Ayudas para estancias en otras universidades o centros de investigación para el año 2017, de la Universidad de CastillaLa mancha (Diario Oficial de Castilla-La Mancha, 2 de Noviembre de 2016, Año XXXV, Número 213, Página 24536). Duration: 3 months. (Grant number: 2016/11635).. 18.

(21) GRANTS AND SOURCES OF FUNDING. -. Ayudas complementarias de movilidad para estancias breves en otros centros españoles y extrajeros, destinadas a beneficiarios del Subprograma de Formación del Profesorado Universitario. (Secretaría. de. Estado. de. Universidades,. Investigación, Desarrollo e Innovación, Resolución de 31 de Agosto de 2018). Duration: 3 months. (Grant number: EST17/00868).. 19.

(22) LIST OF SCIENTIFIC CONTRIBUTIONS. LIST OF SCIENTIFIC CONTRIBUTIONS The present PhD Thesis is composed of a series of studies that have contributed to the scientific literature and have been presented in scientific conferences or seminars:. Main contributions. Study 1 – Journal article Alcazar, J., Aagaard, P., Haddock, B., Kamper, R., Krarup, S., Prescott, E., Alegre, L. M., Frandsen, U., Suetta, C. Age and sex-specific changes in lower-limb muscle power throughout the lifespan. Journal of Cachexia, Sarcopenia and Muscle (under review).. Study 2 – Journal article Alcazar, J., Guadalupe-Grau, A., García-García, F. J., Ara, I., Alegre, L. M. Skeletal muscle power measurement in older people: a systematic review of testing protocols and adverse events. J Gerontol A Biol Sci Med Sci. 2018;73(7):914-924.. Study 3 – Journal article Alcazar, J., Rodriguez-Lopez, C., Ara, I., Alfaro-Acha, A., Mañas-Bote, A., Guadalupe-Grau, A., García-García, F. J., Alegre, L. M. The force-velocity relationship in older people: reliability and validity of a systematic procedure. Int J Sports Med. 2017;38(14):1097-1104.. 20.

(23) LIST OF SCIENTIFIC CONTRIBUTIONS. Study 4 – Journal article Navarro-Cruz, R.*, Alcazar, J.*, Rodriguez-Lopez, C., Losa-Reyna, J., Alfaro-Acha, A., Ara, I., García-García, F. J., Alegre, L. M. The effect of the stretch-shortening cycle in the force-velocity relationship and its association with physical function in older adults with COPD. Front Physiol. 2019;10.3389/fphys.2019.00316. *These authors have contributed equally to this work.. Study 5 – Journal article Alcazar, J., Losa-Reyna, J., Rodriguez-Lopez, C., Navarro-Cruz, R., AlfaroAcha, A., Ara, I., García-García, F. J., Alegre, L. M., Guadalupe-Grau, A. Effects of concurrent exercise training on muscle dysfunction and systemic oxidative stress in older people with COPD. Scand J Med Sci Sports. 2019;10.1111/sms.13494.. Study 6 – Journal article Alcazar, J., Losa-Reyna, J., Rodriguez-Lopez, C., Alfaro-Acha, A., Rodriguez-Mañas, L., Ara, I., García-García, F. J., Alegre, L. M. The sit-tostand muscle power test: an easy, inexpensive and portable procedure to assess muscle power in older people. Exp Gerontol. 2018;112:38-43.. Study 7 – Journal article Alcazar, J., Kamper, R., Aagaard, P., Haddock, B., Prescott, E., Ara, I., Suetta, C. Relation between leg extension power and the 30-s sit-to-stand power test in older adults. Journal of Cachexia, Sarcopenia and Muscle (under review).. 21.

(24) LIST OF SCIENTIFIC CONTRIBUTIONS. Study 8 – Journal article Alcazar, J., Kamper, R., Aagaard, P., Haddock, B., Prescott, E., Ara, I., Alegre, L. M., Suetta, C. Assessment of functional sit-to-stand muscle power: variations across the lifespan. Ready for submission.. Study 9 – Journal article Losa-Reyna, J.*, Alcazar, J.*, Rodríguez-Gómez, I., Alfaro-Acha, A., Alegre, L. M., Rodríguez-Mañas, L., Ara, I., García-García, F. J. Low relative muscle power in older adults: an operational definition and algorithm for its application in daily clinical practice. Journal of Cachexia, Sarcopenia and Muscle (under review). *These authors have contributed equally to this work.. Study 10 – Journal article Alcazar, J., Alegre, L. M., Van Roie, E., Magalhães, J. P., Nielsen, B. R., González-Gross, M., Júdice, P. B., Casajús, J. A., Delecluse, C., Sardinha, L. B., Suetta, C., Ara, I. Relative sit-to-stand muscle power and aging: trajectories, cut-off points, normative data and minimal clinically important differences in a large European cohort. Ready for submission.. 22.

(25) LIST OF SCIENTIFIC CONTRIBUTIONS. Other contributions. Study 2 – Poster presentation Alcazar, J., Guadalupe-Grau, A., García-García, F. J., Ara, I., Alegre, L. M. Evaluación de la potencia muscular en personas mayores: consideraciones metodológicas. Una revisión sistemática. Simposio EXERNET. Investigación en ejercicio, salud y bienestar: exercise is medicine. 14-15th October 2016, Cádiz, Spain.. Study 3 – Oral presentation Alcazar, J., Rodriguez-Lopez, C., Guadalupe-Grau, A., Alfaro-Acha, A., Navarro-Cruz, R., García-García, F. J. Losa-Reyna, J., Ara, I., Alegre, L. M. Perfil fuerza-velocidad y funcionalidad física en las personas mayores: es hora de mirar más allá de la 1-RM. IX Simposio internacional de actualización en entrenamiento de fuerza. 16-17th December 2016, Madrid, Spain.. Study 3 – Poster presentation Alcazar, J., Rodriguez-Lopez, C., Alegre, L. M., Ara, I., García-García, F. J., Guadalupe-Grau, A. Evaluación de la potencia muscular en personas mayores: influencia del ciclo de estiramiento-acortamiento. IX Congreso internacional de la Asociación Española de Ciencias del Deporte (21-23 April 2016, Toledo, Spain).. Study 5 – Oral presentation Alcazar, J., Losa-Reyna, J., Rodriguez-Lopez, C., García-García, F. J., PerezMartinez, A., Espinosa-De Los Monteros, M. J., Alfaro-Acha, A., Alegre, L. M., Ara, I., Guadalupe-Grau, A. Systemic oxidative stress is decreased in. 23.

(26) LIST OF SCIENTIFIC CONTRIBUTIONS. older subjects with COPD after a 12-week exercise program combining HIIT and power training. 23th Annual congress of the European College of Sports Science. 4-7th July 2018, Dublin, Ireland.. Study 6 – Poster presentation Alcazar, J., Losa-Reyna, J., Rodriguez-Lopez, C., Ara, I., García-García, F. J., Alegre, L. M. The sit-to-stand muscle power test: an easy, inexpensive and portable procedure to assess muscle power in older people. Jornadas internacionales de investigación en actividad física y salud. 14th December 2017, Cuenca, Spain.. Study 8 – Oral presentation Alcazar, J., Aagaard, P., Haddock, B., Ara, I., Alegre, L. M., Prescott, E., Hovind, P., Suetta, C. Sit-to-stand muscle power is a sensitive and clinically relevant tool to monitor changes in lower-limb muscle power throughout the lifespan. 24th Annual congress of the European College of Sport Science. 3-6th July 2019, Prague, Czech Republic.. Study 9 - Symposium Alcazar, J. Muscle power: relation to physical function and frailty. 15th International Congress of the European Geriatric Medicine Society. 25-27th September 2019, Kraków, Poland.. 24.

(27) RESEARCH STAYS. RESEARCH STAYS The PhD candidate has completed two research stays in the following destinations:. -. Laboratorio de Fisiología y Rendimiento Humano, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria. Las Palmas de Gran Canaria (Spain). Supervisor: José Antonio López Calbet, PhD. Full professor and head of the research group. Date: from 1st June 2017 to 1st September 2017. Duration: 3 months. Certificate in Appendix 1.. -. Xlab Research Group, Center of Healthy Aging, University of Copenhagen. Copenhagen (Denmark). Supervisor: Jørn Wulff Helge, PhD. Full professor and head of the research group. Date: from 18th September 2018 to 18th December 2018. Duration: 3 months. Certificate in Appendix 2.. 25.

(28) ABSTRACT. ABSTRACT Background The aging of the global population has led to a dramatic increase in the number and proportion of people experiencing mobility limitations at old age. The World Health Organization (WHO) has encouraged health systems to prioritize the healthy aging goals of building and maintaining functional ability in order to revert this situation. Muscle power has been found to decline with age at an earlier and faster rate than muscle mass and strength, and is more strongly related with mobility limitations, cognitive decline and mortality. Therefore, the main goals of the present PhD thesis were: 1) to evaluate the pattern and time course of changes in relative muscle power throughout the lifespan in healthy women and men (Study 1); 2) to systematically review the different protocols/instruments used in the literature to assess muscle power in older adults and compare the reliability and validity of several of these protocols (Studies 2 and 3); 3) to analyze the effects of a concurrent exercise training program combining high-intensity interval endurance training and power training on limb muscle dysfunction and systemic oxidative stress in older people with chronic obstructive pulmonary disease (COPD) (Studies 4 and 5); 4) to measure the validity and functional relevance of a clinical tool to assess muscle power in older people (the sit-to-stand (STS) muscle power test) (Studies 6, 7 and 8); and 5) to provide normative data, cut-off points and minimal clinically important difference values for power values obtained by the STS muscle power test (Studies 9 and 10).. 26.

(29) ABSTRACT. Methods The present PhD thesis is composed by 10 studies in which voluntarily participated different cohorts (the “Copenhagen Sarcopenia Study”: 1305 subjects aged 20-93 years; the “EXERNET Multi-center Study”: 2662 subjects aged 65-91 years; a Belgian cohort: 1083 subjects aged 60-93 years; a Portuguese cohort: 4856 subjects aged 65-103 years; and the “Toledo Study for Healthy Aging”: 1804 subjects aged 67-101 years) and groups of older people (in total 79 subjects aged 65-90). Briefly, anthropometrics (body mass and height), body composition (assessed by bio-electrical impedance analysis or dual x-ray absorptiometry) and skeletal muscle size and architecture (assessed by ultrasonography or computed tomography) were evaluated. Muscle power was assessed with the Nottingham power rig and also using an instrumented (linear position transducer) leg press machine. Also, an equation based on the subject’s body mass and height, chair height and performance in the traditional STS test was created (called the STS muscle power test) to estimate muscle power, and its validation against the results obtained from the two above-mentioned instruments was tested. Physical performance and frailty were measured using various functional tests and batteries widely used in the literature (e.g. habitual gait speed, maximal gait speed, timed up-and-go test and 6-min walking test). Moreover, other health-related outcomes such as cognitive function and quality of life were evaluated using validated questionnaires. In the studies conducted in older people with COPD we further measured lung function (spirometry), peak aerobic capacity (incremental cardiopulmonary exercise test) and systemic oxidative stress (plasma protein carbonylation). The COPD subjects were randomly assigned to a 12-week exercise training (combining high-intensity interval training and power training) or a control group. Finally, the systematic review was conducted and reported in. 27.

(30) ABSTRACT. accordance with the PRISMA statement. All the statistical analyses were performed according to standard procedures and the level of significance was set at α = 0.05.. Results Relative muscle power declined above the age of 40 years in both women and men influenced by an increase in body mass index and a decrease in specific muscle power (p<0.05); while above the age of 75 years in women and 65 years in men the decline in relative muscle power was due to the loss of both specific muscle power and leg lean mass (p<0.05). The systematic review showed that major discrepancies in muscle power testing protocols existed in the literature, although they were proved to be relatively safe (one adverse event every 144-658 tests) in older people with a broad range of health and functional states. In this line, we found that registering mean values of force and velocity, conducting 3 attempts per load and assessing at least 3 loads was more reliable than other alternatives (p<0.05). On the other hand, the inclusion of a strength-shortening cycle muscle action increased force and power among older people with COPD (p<0.05), and was negatively correlated with physical performance, skeletal muscle size and pennation angle (p<0.05). Older people with COPD presented lower muscle power values than age-matched healthy controls (p<0.05). The 12-week concurrent exercise program produced positive changes among the COPD subjects in mid-thigh muscle cross-sectional area (+4%), vastus lateralis pennation angle (+19%), peak VO2 uptake (+14%), maximum muscle power (+51%), STS time (‒24%), self-reported health status (+20%) and systemic oxidative stress (‒27%) (p<0.05). Muscle power values derived from the STS muscle power test were observed to be correlated with those obtained from the instrumented leg press equipment. 28.

(31) ABSTRACT. (r=0.72) and the Nottingham power rig (r=0.75) (p<0.001). STS power was better correlated with lean mass, cognitive function and physical performance than other measures such as STS time, number of STS repetitions, handgrip strength and muscle power recorded with the Nottingham power rig (p<0.05). In addition, the pattern of decline in STS power values with age did not differ from that noted for power values registered with a previously validated instrument (p>0.05). Age-adjusted logistic regression analyses showed low relative STS muscle power to be associated with impaired physical function, frailty and poor quality of life in both older men and women and disability in older women, while sarcopenia was only associated with impaired physical function and frailty in older men and disability in older women (p<0.05). Receiver operator characteristic curves (ROC) yielded 2.1 W·kg-1 in women and 2.6 W·kg-1 in men as optimal cut-off points for low relative STS power according to their ability to discriminate between older people with and without mobility limitations (area under the curve = 0.85 and 0.89, respectively) (p<0.05).. Conclusions Relative muscle power declined above 40 years in both women and men, but the main reasons leading to this decline varied throughout the lifespan (Study 1). Importantly, the great variation in muscle power testing protocols noted across studies may limit consensus in the literature (Study 2). Some parameters related with data collection and the number of attempts and loads performed during testing were found to influence reliability and the association between muscle power and physical performance in older adults (Study 3). On the other hand, despite older people with COPD exhibited decreased muscle power values (Study 4), the application of an exercise training program combining high-intensity. 29.

(32) ABSTRACT. interval training and power training improved limb muscle dysfunction and systemic oxidative stress in older people with COPD (Study 5). Finally, our proposed STS muscle power test was found to be valid to assess muscle power in older adults, showed a higher functional relevance compared with other traditionally used measures, and its pattern of change with age did not differ from the one observed using a previously validated instrument (Studies 6, 7 and 8). Furthermore, low relative STS muscle power proved to be more clinically relevant than sarcopenia among older men and women (Study 9), and the reported sex-specific cut-off points for low relative STS muscle power were demonstrated to discriminate satisfactorily between older subjects with and without mobility limitations (Study 10).. 30.

(33) LIST OF TABLES. LIST OF TABLES INTRODUCTION AND JUSTIFICATION Table 1. Life expectancy at birth and at 65 years in various European countries and in the European Union ……... Table 2. Old-age and economic old-age ratios in various European countries and in the European Union …….... Table 3. 47. 47. Healthy life expectancy and years lived with disability at birth in various European countries and in Western Europe ………………………………………. 49. MATERIAL AND METHODS Table 4. Main characteristics of the subjects of the Copenhagen Sarcopenia Study participating in Studies 1, 8 and 10 ……………………………………………………………... Table 5. Main characteristics of the subjects of the Copenhagen Sarcopenia Study participating in Study 7 ……………. Table 6. 86. Main characteristics of the COPD and non-COPD older subjects participating in Study 4 ………………... Table 9. 86. Main characteristics of the community-dwelling older subjects participating in Study 6 ……………………….. Table 8. 85. Main characteristics of the community-dwelling older subjects participating in Study 3 ……………………….. Table 7. 85. 87. Main characteristics of the COPD older subjects randomized in two groups and participating in Study 5 ………………………………………………………….... 31. 88.

(34) LIST OF TABLES. Table 10. Main characteristics of the sub-sample of older subjects from the Toledo Study for Healthy Aging participating in Study 6 …………………………………. Table 11. 89. Main characteristics of the sub-sample of older subjects from the Toledo Study for Healthy Aging participating in Study 9 …………………………………. Table 12. Main characteristics of the older (aged 60.0-103.0 years) female and male participants of Study 10 …….. Table 13. 89. 91. Main characteristics of the young and middle-aged (aged 20.0-59.9 years) female and male participants of Study 10 …………………………………………………... Table 14. 92. Sex-specific tertiles for the different components of the operational algorithm of low relative muscle power in Study 9 ……………………………………….... 110. RESULTS (Study 1) Table 1. Muscle power and body composition measures for women and men by different age groups …………….. Table 2. 153. Annual rate of change in muscle power and body composition parameters in women and men by different age groups ……………………………………... 154. (Study 2) Table 1. Summary. statistics. for. the. different. testing. parameters found in the literature …………………….. Table 2. 163. Intensity at which maximal muscle power was reached for each exercise ………………………………... 32. 165.

(35) LIST OF TABLES. (Study 3) Table 2. Comparison between different protocols and testing sessions to assess the force-velocity relationship and muscle power ……………………………………………. Table 3. Reliability comparison of force-velocity parameters obtained from mean and peak values ………………….. Table 4. 174. 174. Reliability comparison of mean muscle power exerted at 60% 1RM between the single- and the multiplerepetition per set protocols ……………………………... Table 5. 174. Reliability comparison of force-velocity parameters obtained from protocols differing in the number of attempts per load and/or number of loads ……………. 175. (Study 4) Table 2. Comparison of concentric and eccentric-concentric force values at various contraction velocities relative to maximal concentric unloaded shortening velocity ... Table 3. 186. Comparison of concentric and eccentric-concentric power values at various contraction velocities relative to maximal concentric unloaded shortening velocity ... 186. (Study 5) Table 2. Effects of exercise training on cardiopulmonary variables in the study participants …………………….. Table 3. 199. Effects of exercise training on isometric force variables and physical performance in the study participants …. 200. (Study 6) Table 3. Comparison between velocity and muscle power values obtained from the sit-to-stand muscle power test and the leg press force-velocity relationship ……... 33. 210.

(36) LIST OF TABLES. Table 4. Adjusted regression analyses between sit-to-stand measures and age-related outcomes …………………... 211. (Study 7) Table 2. Mean lower limb muscle power assessed by the Nottingham power rig and the 30-s sit-to-stand test …. Table 3. 232. Unadjusted and adjusted regression analyses to identify determinants of maximal horizontal gait speed in the present cohort of elderly-to-old adults ….. 233. (Study 8) Table 1. Sit-to-stand muscle power measures for women and men by different age groups ……………………………. Table 2. 260. Annual rate of change in sit-to-stand muscle power measures in women and men by different age groups. 261. (Study 9) Table 3. Logistic. regression. analysis. comparing. the. association of sarcopenia and low relative sit-to-stand power with other negative outcomes ………………….. 288. (Study 10) Table 3. Comparison of mean characteristics between older subjects with and without mobility limitations ………. Table 4. Sex-specific normative data for relative sit-to-stand muscle power ……………………………………………. Table 5. Table 7. 325. Sex-specific normative data for absolute sit-to-stand muscle power ……………………………………………. Table 6. 324. 326. Sex-specific normative data for specific sit-to-stand muscle power ……………………………………………. 327. Sex-specific normative data for body mass index ……. 328. 34.

(37) LIST OF TABLES. Table 8. Sex-specific normative data for legs skeletal muscle index …………………………………………………….... Table 9. 329. Optimal cut-off points to discriminate between older subjects with and without mobility limitations, and sensitivity and specificity values ………………………. 330. DISCUSSION Table 15. Comparison of the reliability values (coefficient of variation) found in the present investigation with those reported in the literature …………………………. Table 16. 357. Comparison of the reliability values (intra-class correlation. coefficient). found. in. the. present. investigation with those reported in the literature ….... 35. 358.

(38) LIST OF FIGURES. LIST OF FIGURES INTRODUCTION AND JUSTIFICATION Figure 1. Functional trajectories during the aging process …….. Figure 2. Adapted functional ability model based on the ICF model and the healthy aging model …………………... Figure 3. 51. 52. Structural complexity of skeletal muscles and characteristic changes attributed to sarcopenia ………. 56. MATERIAL AND METHODS Figure 4. Ultrasound image obtained from the vastus lateralis muscle of a standard subject ……………………………. Figure 5. 94. Hierarchical classification of variables accounting for relative muscle power …………………………………... 110. RESULTS (Study 1) Figure 1. Trajectories of absolute, relative and specific leg extension power values throughout the lifespan in women and men …………………………………………. Figure 2. 156. Trajectories of body mass index and relative leg lean mass values throughout the lifespan in women and men ……………………………………………………….. 157. (Study 2) Figure 1. Figure 2. Flow diagram on identification, screening, eligibility, and inclusion of full-text articles ……………………….. 162. Risk of reporting bias across studies ………………….... 164. 36.

(39) LIST OF FIGURES. Figure 3. Resistance exercises and testing parameters for muscle power testing in older adults reported in the literature ………………………………………………….. 164. (Study 4) Figure 2. Differences. between. concentric. and. eccentric-. concentric force and power values exerted at different absolute contraction velocities in COPD and healthy older participants ……………………………………….. Figure 3. Differences. between. concentric. and. 185. eccentric-. concentric force, velocity and power values across the range of movement at a low and a high intensity ……. 187. (Study 5) Figure 1. Participant. flow. from. recruitment. to. study. completion ………………………………………………. Figure 2. 197. Effects of the exercise training program on mid-thigh composition obtained from computed tomography scans ………………………………………………………. Figure 3. 198. Effects of the exercise training program on vastus lateralis muscle thickness and architecture obtained from ultrasound images ……………………………….... Figure 4. 198. Effects of the exercise training program on leg press and chest press outcomes obtained from the forcevelocity relationship of the participants ……………….. Figure 5. 201. Individual and average responses to the exercise training program or control period regarding blood protein carbonylation levels ……………………………. 37. 201.

(40) LIST OF FIGURES. (Study 6) Figure 1. Bland-Altman plot for muscle power measures obtained from the sit-to-stand test and the leg press exercise ………………………………………………….... 210. (Study 7) Figure 1. Pearson correlation plots for the association between unilateral lower limb muscle power measures obtained from the Nottingham power rig and the sitto-stand test ………………………………………………. Figure 2. 235. Bland-Altman plots for lower limb muscle power measures obtained from the Nottingham power rig versus the sit-to-stand test …………………………….... 236. (Study 8) Figure 1. Trajectories of absolute, relative and specific sit-tostand power values throughout the adult lifespan in women and men …………………………………………. Figure 2. 262. Comparison of trajectories of relative muscle power between leg extension power (Nottingham power rig) and sit-to-stand muscle power in women and men included in the same study cohort …………………….. 263. (Study 9) Figure 2. Comparison of habitual gait speed and frailty levels among various groups of older men and women without sarcopenia or low relative sit-to-stand power, sarcopenia, low relative sit-to-stand power, and both sarcopenia and low relative sit-to-stand power ………. Figure 3. Comparison of habitual gait speed and frailty levels among various groups of older men and women. 38. 290.

(41) LIST OF FIGURES. combining different levels of absolute sit-to-stand power and body mass index …………………………… Figure 4. 291. Comparison of habitual gait speed and frailty levels among various groups of older men and women combining different levels of specific sit-to-stand power and legs skeletal muscle index …………………. 292. (Study 10) Figure 1. Comparison between older subjects with and without mobility limitations regarding sit-to-stand power measures and legs skeletal muscle index, separately in women and men …………………………………….... Figure 2. Trajectories of relative sit-to-stand muscle power throughout the lifespan in women and men ………….. Figure 3. 331. 332. Receiver operator characteristic curve plot for women and for men ………………………………………………. 333. DISCUSSION Figure 6. Individual. response. observed. among. COPD. participants in terms of strength-shortening cycleinduced potentiation in force values at 20% of V0 and 80% of V0 …………………………………………………. Figure 7. 362. Comparison of trajectories of relative muscle power between leg extension power and sit-to-stand muscle power in women and men included in the same study cohort ……………………………………………………... Figure 8. 384. Flowchart to detect low relative muscle power and its causes ……………………………………………………... 39. 392.

(42) LIST OF FIGURES. Figure 9. Updated operational algorithm to identify low relative muscle power and its causes …………………... 40. 400.

(43) LIST OF ABBREVIATIONS. LIST OF ABBREVIATIONS Abbreviations are defined at first mention and used consistently thereafter: θ. Pennation angle. 1RM. One repetition maximum. 2+1. Two attempts plus an additional attempt. 3-L. Three loads. 6-MWD. 6-min walking distance. AE. Adverse event. ASMI. Appendicular skeletal muscle index. AUC. Area under the curve. BADL. Basic activities of daily living. BMI. Body mass index. BODE. Body mass index, obstruction, dyspnea and exercise. BW. Body weight. CI. Confidence interval. CL. Confidence limit. CSA. Cross-sectional area. CT. Control group. CV. Coefficient of variation. COPD. Chronic obstructive pulmonary disease. DNP. Dinitrophenylhydrazone. DNPH. Dinitrophenylhydrazine. DXA. Dual energy X-ray absorptiometry. EDTA. Ethylenediaminetetraacetic acid. ES. Effect size. ET. Exercise training group. EU27. European Union with 27 member states. 41.

(44) LIST OF ABBREVIATIONS. EWGSOP. European Working Group on Sarcopenia in Older People. F0. Force-intercept. F-V. Force-velocity. FEV1. Forced expiratory volume in one second. FL. Fascicle length. FTS. Frailty Trait Scale. FVC. Forced vital capacity. GS. Gait speed. HIIT. High-intensity interval training. HLE. Healthy life expectancy. HRQoL. Health-related quality of life. HU. Hounsfield units. IADL. Instrumental activities of daily living. ICC. Intra-class correlation coefficient. ICD-10-CM. International Classification of Diseases, Tenth Revision, Clinical Modificatio. ICF. International Classification of Functioning, Disability and Health. LEP. Leg extension power. Lopt. Optimal load. M-L. Multiple-load. MCID. Minimal clinically important difference. MIF. Maximal isometric force. MMSE. Mini-mental state examination. MR. Multiple-repetition. MT. Muscle thickness. MVIC. Maximal voluntary isometric contraction. OR. Odds ratio. Pmax. Maximum muscle power. PRISMA. Preferred Reporting Items for Systematic Reviews and Meta-analyses. 42.

(45) LIST OF ABBREVIATIONS. PVDF. Polyvinylidene difluoride. R2. Coefficient of determination. RFD. Rate of force development. ROC. Receiver operator curve. ROM. Range of movement. RONS. Reactive oxygen and nitrogen species. SD. Standard deviation. SEE. Standard error of the estimate. SEM. Standard error of measurement. SFV. Slope of the force-velocity relationship. SMI. Skeletal muscle index. SpO2. Peripheral capillary oxygen saturation. SPPB. Short physical performance battery. SR. Single-repetition. SSC. Stretch-shortening cycle. STS. Sit-to-stand. TSHA. Toledo Study for Healthy Aging. V0. Velocity-intercept. VAS. Visual analogue scale. VL. Vastus lateralis. VO2peak. Veak pulmonary oxygen uptake. WHO. World Health Organization. Wpeak. Peak work-rate. YLD. Years lived with disability. *Additional abbreviations are defined at first mention and used consistently thereafter within the manuscript of each presented study.. 43.

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(47) CHAPTER 1. INTRODUCTION AND JUSTIFICATION.

(48) INTRODUCTION AND JUSTIFICATION. A. GING may be defined as the time-dependent functional decline that affects most living organisms (1). The general cause of aging. is considered to be the time-dependent accumulation of cellular damage provoked by different physiological sources (1). Aging usually leads to major changes in body structures/functions, in the ability to perform activities of daily living, and in the participation in life. Notably, great changes in the age structure of the European Union population are projected in the coming decades (2). These facts have provoked an exponential increase in the interest that global and local organizations have in aging and its consequences.. 1.1 The population aging in numbers Life expectancy at birth is expected to increase from 76.8 years in males and 82.6 years in females in 2016 to, respectively, 86.1 and 90.3 years in 2070 (Table 1) (2). In this line, life expectancy at 65 years is expected to increase by 29% in males (from 18.0 to 23.4 years) and 24% in females (from 21.6 to 26.7 years) between 2016 and 2070 (2). These changes coupled with an insufficient increase in the number of births and the projected migration trends will contribute to a dramatic aging of the population in Europe. The proportion of people aged 65 years or older will reach 42% by 2070, in comparison with the current proportion registered in the European Union (25%) (2). This tremendous increase in the proportion of older adults will be translated into an increment in the proportion of older people relative to those aged 15-64 (i.e. the old age dependency ratio), which is projected to increase from 29.6% to 51.2% between 2016 and 2070 (Table 2). Furthermore, if we only consider the proportion of inactive older people. 46.

(49) INTRODUCTION AND JUSTIFICATION. Table 1. Life expectancy at birth and at 65 years in various European countries and in the European Union. Region. Belgium. Denmark. Portugal. Spain. EU27. Sex. Life expectancy at birth (years). Life expectancy at 65 (years). 2016. 2070. Change. 2016. 2070. Change. Men. 78.8. 86.2. 7.4. 18.3. 23.4. 5.1. Women. 83.7. 90.2. 6.5. 21.7. 26.6. 4.9. Men. 78.8. 86.1. 7.3. 18.1. 23.3. 5.2. Women. 82.9. 90.0. 7.1. 20.8. 26.4. 5.6. Men. 78.2. 85.9. 7.7. 18.1. 23.3. 5.2. Women. 84.3. 90.4. 6.1. 21.8. 26.7. 4.9. Men. 80.5. 86.9. 6.4. 19.3. 23.9. 4.6. Women. 86.0. 91.2. 5.2. 23.2. 27.3. 4.1. Men. 78.1. 86.1. 7.9. 18.0. 23.4. 5.3. Women. 83.7. 90.3. 6.6. 21.6. 26.7. 5.1. Note: EU27: European Union with 27 member states. Adapted from (2).. Table 2. Old-age and economic old-age ratios in various European countries and in the European Union. Region. Old-age dependency ratio (%) 2016. 2070. Change. Economic old-age dependency ratio (%) 2016. 2070. Change. Belgium. 28.4. 45.2. 16.7. 45.0. 66.7. 21.7. Denmark. 29.5. 50.2. 20.8. 38.4. 59.4. 21.0. Portugal. 32.1. 67.2. 35.1. 45.3. 84.1. 38.8. Spain. 28.6. 46.6. 18.0. 47.4. 60.9. 13.6. EU27. 29.6. 51.2. 22.4. 44.2. 70.7. 26.5. Note: EU27: European Union with 27 member states. Adapted from (2).. 47.

(50) INTRODUCTION AND JUSTIFICATION. and the number of employed people (i.e. the economic old age dependency ratio), the ratio will rise from 44.2% in 2016 to 70.7% in 2070 in the European Union (Table 2). Thus there will be approximately 3 persons employed for 2 inactive older persons. These measures are good indicators of the impact that the aging of the population will have on the economy and social structure. Importantly, this fact will bring major consequences related with the coverage of pensions and the increment in the use of health-care and long-term resources by older people, and entails a substantial challenge to the long-term sustainability of public finances and services. Accordingly, several countries have already carried out several reforms related with the expansion of the statutory retirement age or the state pension age. However, additional reforms and new policies are/will be required in the present/future.. 1.2 Towards a more disabled older population It is well-known that the demographic transition to older populations will take place in the near future. Fortunately, older people can contribute to society to many ways (within their family, local community and society more broadly), but the extent of these contributions and the opportunities available to older people will be heavily dependent on their health. If the additional years lived are dominated by declines in physical and cognitive capacities, not only the potential contribution of older people to society will be limited, but the consequences to society and to the individual per se will be much more negative. Although life expectancy has been shown to increase substantially during the last decades, the number of years lived in good health (i.e. without disability) has not increased to the same extent (3). People aged 50-. 48.

(51) INTRODUCTION AND JUSTIFICATION. 70 years experiences on average a ~30% decline in gait speed and chair stand ability, while the decrement is observed to reach ~50% in people aged 70 years and older, compared with their younger counterparts (4). These increasing limitations hinder the participation of older people in activities of daily living. Importantly, impaired physical function in mid-life predicts the incidence of disability at old age (5). Thus the number of years lived in poor health/disability has been reported to increase by 1.4 years (from 8.7 to 10.1 years) in men and 1.1 years (from 11.3 to 12.4 years) in women living in Western Europe from 1990 to 2017 (6) (Table 3).. Table 3. Healthy life expectancy and years lived with disability at birth in various European countries and in Western Europe. Region. Sex. HLE at birth (years). YLD at birth (years). 1990. 2017. Change. 1990. 2017. Change. Men. 63.9. 69.1. 5.2. 8.8. 9.8. 1.0. Women. 67.8. 70.9. 3.1. 11.5. 12.9. 1.4. Men. 63.7. 68.6. 4.9. 8.5. 10.2. 1.7. Women. 66.9. 70.6. 3.7. 10.9. 12.1. 1.2. Men. 62.1. 68.6. 6.5. 8.6. 9.9. 1.3. Women. 66.2. 71.6. 5.4. 11.4. 12.6. 1.2. Men. 65.0. 70.5. 5.5. 8.5. 9.7. 1.2. Women. 69.4. 73.6. 4.2. 11.1. 12.2. 1.1. Western. Men. 64.0. 68.2. 4.2. 8.7. 10.1. 1.4. Europe. Women. 68.2. 71.8. 3.6. 11.3. 12.4. 1.1. Belgium. Denmark. Portugal. Spain. Note: HLE, healthy life expectancy. YLD, years lived with disability. Adapted from (6).. In this sense, the European Union has established the promotion of active aging as one of the most important initiatives to reduce the negative consequences of the progressive aging of the population (3). This initiative. 49.

(52) INTRODUCTION AND JUSTIFICATION. aims to facilitate the active participation of older people in society and economy, and to reduce the health-care and long-care costs associated with disability or health worsening with age. Specifically, this initiative targets to augment the healthy lifespan by two years by 2020, in order to enable older people to live healthier and more independent lives, and improve sustainability and efficiency of health and care systems (3).. 1.3 Functional ability as the core component of healthy aging The World Health Organization (WHO) defines healthy aging as the process of developing and maintaining the functional ability that enables well-being in older age (7). Importantly, the WHO has proposed a new older-person-centered and integrated care model in which health systems are encouraged to prioritize the healthy aging goals of building and maintaining functional ability (7) over other traditional approaches focused on multimorbidity. This is supported by previous studies showing that limitations in functional ability are more strongly associated with mortality and health-care costs than multimorbidity (8-10). Functional ability comprises the health-related attributes that enable people to be and to do what they have reason to value, and depends on the individual’s intrinsic capacity (composite of all the physical and mental capacities) and environment (factors in the extrinsic world that form the context of an individual’s life), and the interaction between these characteristics (7). For example, a decrement in intrinsic capacity with age (e.g. decreased lowerlimb strength) that affects functional ability (e.g. the ability to climb/descend the stairs to enter/leave home) can be accompanied by a transformation of the environment (e.g. installation of a handrail), so that. 50.

(53) INTRODUCTION AND JUSTIFICATION. the loss of intrinsic capacity can be partially compensated (e.g. the individual can still ascend/descend the stairs safely to enter/leave home) (Figure 1). Nevertheless, it is intrinsic capacity which usually determines to a greater extent functional ability. For this reason, the WHO has announced that the main role of health systems is to optimize trajectories of intrinsic capacity (7).. Figure 1. Functional trajectories during the aging process. Subject A (healthy aging trajectory; blue solid lines) exhibits an optimal trajectory, with functional ability and intrinsic capacity being relatively well maintained until the end of life. On the contrary, subject B (unhealthy aging trajectory; red dashed lines) experiences an earlier decline in both functional ability and intrinsic capacity. Subject B will live a greater number of years with frailty and disability (grey dashed horizontal lines from up to down, respectively), while subject A will avoid frailty and disability until the end of life. Arrows indicate the effect of the interaction between the individual’s intrinsic capacity and environment. Intrinsic capacity has been reported to capture the notion of body structures and functions contained in the International Classification of Functioning, Disability and Health (ICF) model (11). According to the ICF model, impairments in one or various body structures/functions (i.e., intrinsic capacity) can lead to limitations in activities of daily living and restrict the participation in daily life situations (i.e., functional ability) (12). Above a certain threshold, these limitations can lead to the onset of frailty. 51.

(54) INTRODUCTION AND JUSTIFICATION. and disability (Figure 2). Frailty is a syndrome determined by a decreased reserve of intrinsic capacity and an extreme vulnerability to stressors (7). Approximately 1 in 10 older adults are frails and 1 in 3 older adults are prefrails (the state that precedes frailty) (13). Frailty is associated with a higher incidence of falls, hospitalization, institutionalization and mortality, and can be considered an intermediate phase of the disabling cascade (14-16). Disability is considered an umbrella term that is present in people with severe impairments, activity limitations, and participation restrictions (12). Fortunately, the path toward disability is amenable to modification, and thus both pre-frailty and frailty can be reverted (17).. Figure 2. Adapted functional ability model based on the ICF model (12) and the healthy aging model (7). An impairment in a body structure or function that is not compensated by environmental factors can produce limitations in activities of daily living and restrictions in participation in life. These activity limitations and participation restrictions can lead to frailty, which precedes the onset of disability. Therefore, healthy aging and disability are two different sides of the same coin. Consequently, the maintenance and improvement of intrinsic capacity during aging, in order to postpone frailty and disability as late as possible in life, have become a public health priority (16). In this sense, the identification and understanding of the biological causes and mechanisms. 52.

(55) INTRODUCTION AND JUSTIFICATION. accounting for the age-related deterioration of intrinsic capacity is key, as well as the identification and promotion of effective countermeasures to prevent or revert the loss of intrinsic capacity with age (3).. 1.4 The impact of skeletal muscle structure and function in functional ability There is a vast number of studies supporting the notion that skeletal muscles determine to a great extent intrinsic capacity and functional ability. Skeletal muscles normally account to approximately 40% of total body mass in humans, and are mainly composed of water (75%), proteins (20%) and inorganic salts, minerals, fat and carbohydrates (5%) (18). Skeletal muscles accomplish very important hemodynamic and metabolic functions by favoring venous return, respiratory integrity, insulin sensitivity and glucose management, drug tolerability, and energy and amino acid provision (19-21). In addition, the cross-talk between the central nervous system and skeletal muscles, and the attachment of the latter to bones by means of tendons, confer skeletal muscles the ability to produce mechanical work (i.e. force and movement). Muscle contraction occurs due to the interaction among contractile proteins (mainly actin, myosin and titin) following muscle excitation by motor neurons and energy availability (for further reading: (22-25)). Muscle force is transmitted through tendons to bones, which hopefully will make joints rotate, and so generating movement. For these reasons, the deterioration of skeletal muscles contributes enormously to the decline in functional ability most frequently observed during aging, as stated in the following sections.. 53.

(56) INTRODUCTION AND JUSTIFICATION. 1.4.1 Sarcopenia The term ‘sarcopenia’ was first coined in 1989 by Irwin Rosenberg to describe the decline in muscle mass caused by aging (26). Sarcopenia was found to be associated with an increased risk of mobility limitations and disability among older adults (27-29). These first findings were based on the assumption that the observed declines in muscle mass were directly related with the loss of muscle strength with age, which would explain the relation between sarcopenia and disability. However, longitudinal studies showed that the age-associated changes in muscle mass only explained about 5% of the variance in the change in muscle strength with aging (30, 31). In that case the original definition of sarcopenia might be insufficient to explain the age-related changes that occur in skeletal muscles, since changes in muscle quality occurring during aging have also negative consequences on functional performance (32, 33). Muscle strength was found to decline earlier and more steeply (‒1.5 to ‒2.0% per year) in life than muscle mass (‒0.5 to ‒1.0% per year) (34), to be more strongly associated with poor functional mobility than muscle mass (34, 35), and to be an independent predictor of incident mobility limitations (36) and mortality (37) in older people, while muscle mass was not. These findings contributed to suggest that measures of muscle mass should be complemented with measures of strength for a better management of sarcopenia (34, 38, 39). On the other hand, the disassociation between muscle size and muscle strength might also be due to the inherent structural complexity of skeletal muscles. Skeletal muscles are composed by tens to thousands of single muscle fibers that can be arranged in different ways (muscle architecture) (40). There are three general classes of muscle fiber architecture: parallel, unipennate and multipennate. Unipennate and. 54.

(57) INTRODUCTION AND JUSTIFICATION. multipennate muscles present fibers that are oriented at a certain angle relative to the force-generating axis of the muscle (40). Upon adequate excitation, muscle force is mainly dependent on the number and size of activated muscle fibers in parallel, which is represented by the physiological cross-sectional area (CSA) (41), and not merely by the anatomical CSA or the amount of muscle mass, which are most frequently measured in the literature. In this sense, when the physiological CSA of skeletal muscles is regarded, muscle weakness at older age has been mainly attributed to the loss of single ‒ type I and II ‒ muscle fibers and atrophy of the remaining ‒ type II ‒ fibers (42) (Figure 3). However, the fact that the older subjects exhibit decreased specific (normalized to physiological CSA) force values compared to young subjects indicates that other factors, such as lowered single fiber specific tension (43) or impaired motor unit function (44) occurring earlier in life (middle age), may also contribute to muscle weakness at older age. In any case, sarcopenia has been most recently defined as the decline in muscle mass and strength that occurs with aging (34, 45, 46). Although other authors postulated that there should exist a differentiation between sarcopenia and ‘dynapenia’ (age-related loss of muscle strength) (47, 48), the definition of sarcopenia as the age-related loss of both muscle mass and strength/function has prevailed (49-55). The operational definition provided by the European Working Group on Sarcopenia in Older People (EWGSOP) has been so far the most used definition (50), which has recently been updated (EWGSOP2) (56). Sarcopenia is currently defined as a syndrome characterized by progressive and generalized loss of muscle strength and mass, and its diagnosis requires low muscle strength plus low muscle mass (56). In 2016 sarcopenia was recognized as a disease entity with its inclusion in the ICD-10-CM (International. 55.

(58) INTRODUCTION AND JUSTIFICATION. Classification of Diseases, Tenth Revision, Clinical Modification) (57), which was conformed as an important first step for gaining recognition among clinicians and other health professionals and encouraging the development of effective treatments (58).. Figure 3. Structural complexity of skeletal muscles and characteristic changes attributed to sarcopenia. A According to how single muscle fibers are arranged along skeletal muscles, these can be mainly classified as parallel or pennate. Anatomical (thick red line) and physiological (thick green line) cross-sectional areas (CSA) are the same in parallel muscles but they can differ substantially in pennate muscles. B Physiological muscle CSA decreases during aging as a consequence of the loss of type I (dark red polygon) and II (light red polygon) muscle fibers and atrophy of type II muscle fibers. C Decrements in physiological cross-sectional area coupled with other changes in single fiber specific tension or motor unit function contribute to muscle weakness noted in old sarcopenic individuals.. 1.4.2 Muscle power Muscle power is an attribute of muscle function different from muscle strength that represents the rate at which mechanical work is done (or the. 56.

(59) INTRODUCTION AND JUSTIFICATION. product of force and velocity). In spite of the main research focus has been put on sarcopenia when investigating the consequences of aging on muscle function and functional ability, there exist several reasons for which increasing attention should be paid to muscle power: i) it declines with aging at an earlier and faster rate than muscle mass and strength (3% vs 2% vs 1% per year, respectively) (34, 59-66); ii) it is more strongly related to mobility limitations than muscle mass, muscle strength or maximal aerobic capacity (67-69); iii) it has been found to predict 10-y cognitive decline and brain atrophy (70); and iv) it is more strongly related with mortality than muscle mass and strength (71). The loss of muscle power leads to an augmented risk for falling (72) and a 1-standard deviation (SD) decrease in muscle power has been associated to a 27-42% increased likelihood of disability among older people (73). Several neuromuscular factors such as the preferential atrophy of type II muscle fibers and reductions in excitation rate (42, 63, 74, 75) might particularly contribute to the loss in muscle contraction velocity, and help explain why muscle power is more severely affected by aging in comparison with muscle size and strength (i.e. sarcopenia). Accordingly, the detection of critical periods throughout the lifespan in which muscle power is severely reduced may be useful in identifying and targeting specific age groups who may require intervention to prevent functional loss and disability in late life. Nevertheless, the specific time course of the age-related changes in muscle power remains poorly understood. The report of changes in muscle power with age based on average values from different age groups (61, 74, 76, 77) yields information regarding the age interval at which muscle power deviates from a younger reference group, but it does not provide accurate information about the specific age at which muscle power begins to decline,. 57.

(60) INTRODUCTION AND JUSTIFICATION. which may be of great importance for implementing effective intervention countermeasures. Consequently, regression analysis and the detection of accelerated changes in the slope of the relationship between muscle power and age may provide relevant information about the onset of muscle power decline with age. However, inconsistent data exist in the literature on the specific shape of the relationship describing maximal muscle power as function of increasing age. Although the reduction in muscle power with age has been reported to be linear in several investigations (60, 62, 64-66, 78, 79), studies including a considerably larger number a subjects (n > 1000) have demonstrated a curvilinear relationship, with muscle power declining at a progressively increasing rate with advancing age (34, 80). Lower-limb muscle power has been shown to increase from childhood to reach peak values at the age of 20-30 yrs (76, 81), after which it was found to be nearly maintained in individuals up to 40 years old, and then declined linearly to the end of life (80). However, it has not been tested whether the slope of the relationship between muscle power and age is subjected to change at different age intervals throughout the lifespan and not just reflecting an increase at a single age point. The finding of different rates of loss of muscle power throughout the lifespan might be useful, not just to determine the onset of muscle power decline, but also to identify critical periods in life in which muscle power is lost at an accelerated rate of decline. On the other hand, sex differences in muscle power can be detected during adolescence (~15 years) (76) and are maintained during adulthood, but at some point during old age ( 70 years) these differences become negligible (64, 78). These observations suggest that a different pattern of change in lower limb muscle power may exist between women and men at old ages, which has not been assessed in previous studies (80). This type of information is of special relevance to identify opportunity windows in life to intervene. 58.

(61) INTRODUCTION AND JUSTIFICATION. before the onset of accelerated muscle power decline or in phases in which muscle power declines precipitously. Notably, interventions aimed at preventing or postponing the loss of muscle power later in life may be effective in improving individuals’ quality of life (82) and reducing the economic costs associated with muscle dysfunction at old age (83, 84). Finally, muscle power normalized to body mass (i.e. relative muscle power) has been reported to be more relevant for physical performance than muscle power per se (59, 85, 86) given that a subject’s own body mass is supported during major activities of daily living such as walking, chairrising or stair-climbing. Remarkably, changes in both muscle power and body mass with aging may influence the trajectory of relative muscle power with aging, which might differ from that observed for absolute (i.e. nonnormalized to body mass) muscle power. Furthermore, changes in absolute muscle power with age might be caused by changes in muscle mass or changes in power production per unit of muscle mass (i.e. specific power) (61). The identification of the main factors contributing to the loss of relative muscle power over the lifespan will be of major relevance for the development of effective preventive strategies to counteract the negative effect of aging on skeletal muscle function.. 1.5 Assessment of muscle power in older adults There is no consensus about an adequate protocol to evaluate muscle power in older adults. Investigations aiming at explaining the different mechanisms involved in the loss of muscle power with aging have proliferated in recent years using highly sophisticated techniques of genetic, hormonal and metabolic analysis (87-91), while little attention has been paid to the methodology used for assessing muscle power. This issue. 59.