Calorie restriction rescues mitochondrial dysfunction in Adck2-Deficient skeletal muscle

ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.This work was supported by Junta de Andalucía grant BIO-177, the Instituto de Salud Carlos III FIS grant FIS PI20/00541, CIBERER (U729)-ISCIII, the FEDER Funding Program from the European Union and the Spanish Ministry of Science, Innovation and Universities grant RED2018-102576-T. This work was supported by the Spanish Ministry of Education, Culture and Sports through fellowship FPU16/03264 to JH-C, and the Association Française contre les Myopathies (AFM) through fellowship grant #22450 to CV-G. This work was funded in part by the Intramural Research Program of the National Institute on Aging, NIH. This research was also supported by the Instituto de Salud Carlos III (PI19/01310) (Co-funded by the European Union) and by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2017: SGR 1428) and the CERCA

Health benefits of late-onset metformin treatment every other week in mice

Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans

Age-dependent impact of two exercise training regimens on genomic and metabolic remodeling in skeletal muscle and liver of male mice

Skeletal muscle adapts to different exercise training modalities with age; however, the impact of both variables at the systemic and tissue levels is not fully understood. Here, adult and old C57BL/6 male mice were assigned to one of three groups: sedentary, daily high-intensity intermittent training (HIIT), or moderate intensity continuous training (MICT) for 4 weeks, compatible with the older group’s exercise capacity. Improvements in body composition, fasting blood glucose, and muscle strength were mostly observed in the MICT old group, while effects of HIIT training in adult and old animals was less clear. Skeletal muscle exhibited structural and functional adaptations to exercise training, as revealed by electron microscopy, OXPHOS assays, respirometry, and muscle protein biomarkers. Transcriptomics analysis of gastrocnemius muscle combined with liver and serum metabolomics unveiled an age-dependent metabolic remodeling in response to exercise training. These results support a tailored exercise prescription approach aimed at improving health and ameliorating age-associated loss of muscle strength and function in the elderly.This work was supported by funding from the Intramural Research Program of the National Institute on Aging/NIH. Work in JMV laboratory was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) grant BFU2015-64630-R, Ministerio de Ciencia, Innovación y Universidades (MICIU) grant RTI2018-100695-B-I00, Spanish Junta de Andalucía grants P18-RT-4264, 1263735-R and BIO-276, the FEDER Funding Program from the European Union, and Universidad de Córdoba. MCR was supported by a FPU fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (reference FPU14/06308). SRL held a FPI predoctoral contract funded by MINECO (reference BES-2016-078229).Peer reviewe

Differential influence of anaerobic and aerobic exercises in aging

Programa de Doctorado en Ciencias de la Actividad Física y del DeporteLínea de Investigación: Nutrición y Ejercicio FísicoClave Programa: DAFCódigo Línea: 36El envejecimiento causa un deterioro continuado de los tejidos y órganos que les lleva a la perdida de las funciones particulares y de la integración entre ellos. Este deterioro lleva a un estado de fragilidad general asociada a la disfunción muscular que conduce a la sarcopenia y a la aparición de enfermedades degenerativas como Parkinson y Alzheimer. Las causas más importantes de este deterioro general viene dado por la disfunción mitocondrial asociada a la pérdida de sensibilidad a los nutrientes, disminución de la eliminación de proteínas defectuosas, pérdida de la capacidad de regeneración de las células madres y el aumento de la senescencia celular junto a la disminución de la comunicación intercelular, así como la inestabilidad genómica asociada al desgaste del telómero y a la alteración epigenética. Se han descrito intervenciones nutricionales no genéticas como la restricción calórica, y compuestos que actúan como miméticos, que retrasan o restauran estas funciones y aumentan la longevidad y la salud durante la vejez. Entre estas intervenciones se ha descrito el beneficio causado por el ejercicio en algunas de estas funciones particularmente sobre la pérdida de la capacidad muscular, la integración metabólica entre el músculo y el tejido graso, y la mejora de la capacidad cerebral como la memoria. Los estudios realizados hasta la fecha apuntan al beneficio para la salud general y particularmente para la integridad y funcionamiento muscular. Sin embargo, bajo el concepto de ejercicio se incluyen distintas intensidades, distinto nivel de regularidad y de duración lo que determina además la mayor o menor dependencia del consumo de oxígeno lo que hace difícil de disponer de una estrategia a la hora de asesorar el tipo de ejercicio recomendado según la edad y el estado de salud/metabólico de cada individuo. Nuestro trabajo trata de responder a las siguientes preguntas: ¿Depende la adaptación al ejercicio de la edad? ¿Depende la adaptación al ejercicio de la intensidad de éste? ¿Puede el ejercicio de alta intensidad proporcionar el mismo beneficio que el causado por el ejercicio de resistencia? Para responder a estas preguntas hemos diseñado un abordaje simultáneo de intervenir en ratones C57BL6 jóvenes (5 meses) y viejos (23 meses) con dos tipos de ejercicios: anaeróbico y agudo (3x2 min a 27 m/min) (sprint) comparado con aeróbico y crónico (45 min a 13 m/min) (resistencia) entrenados durante cuatro semanas. Las características de los ejercicios fueron confirmadas por las cámaras metabólicas y el contenido de metabolitos en el plasma. Los dos ejercicios no tuvieron efectos sobre la composición corporal o la fuerza muscular en los ratones jóvenes pero tuvo un efecto positivo en los ratones viejos ya que disminuyeron el peso por pérdida de grasa y aumento la fuerza muscular lo que confirma el beneficio del ejercicio en la vejez. El ejercicio aeróbico/crónico activó las rutas de señalización del AMPK y de la insulina tanto en los ratones jóvenes como en los viejos. Sin embargo, el ejercicio anaeróbico/agudo indujo un efecto diferente según la edad: no tuvo efecto sobre el músculo de los animales jóvenes pero activó de forma significativa la ruta de la insulina y una tendencia a aumentar la ruta del AMPK en el músculo de los animales viejos, lo que confirma que estos últimos tienen las capacidades disminuidas y que la actividad física las puede mejorar. La activación de la ruta de la insulina en los animales de las dos edades por el ejercicio crónico/aeróbico y en los animales viejos por el ejercicio agudo/anaeróbico indujo la translocación del transportador GLUT4, dependiente de la insulina, a la membrana plasmática y la disminución del transportador independiente de la insulina GLUT1, lo que demuestra el cambio hacia un transportador regulado que incorpora glucosa desde una concentración limitada. La activación de la ruta de la insulina junto al aumento de GLUT4 indicaría un aumento de la glucólisis para modular el equilibrio redox y la recuperación energética en el músculo después del ejercicio. Nuestros resultados demuestra un aumento de la glucólisis en el músculo de los animales viejos después de los dos ejercicios y en el delos ratones jóvenes después del ejercicio aeróbico/crónico. Estos resultados se explican por la activación final de mTOR que participa en la regulación de los genes glicolíticos. Como consecuencia de la necesidad de recuperación energética en el músculo esquelético por el ejercicio, hemos estudiado la dinámica y funciones mitocondriales. Hemos comprobado que los dos ejercicios producen un aumento de la fisión mitocondrial en las dos edades debido al aumento de la forma activa LC3II y la disminución tanto del marcador mitocondrial VDAC como de la actividad citrato sintasa. Al mismo tiempo se produce un aumento dePGC1a regulador de la biogénesis mitocondrial. Por otro lado, la adaptación de lasa funciones mitocondriales fue diferente como respuesta a los dos ejercicios. El ejercicio agudo/anaeróbico indujo la cadena respiratoria dependiente de NADH activando la actividad y expresión de los complejos I, III y IV en el músculo de los animales jóvenes y el complejo I en los animales viejos. Por otra parte, el ejercicio crónico/aeróbico sólo indujo la activación tanto de la expresión como de la actividad del complejo II que recibe los electrones del succinato mediante FADH2. Estos resultados indican que el ejercicio agudo/anaeróbico selecciona la ruta bioenergética dependiente de la glucosa durante la recuperación muscular mientras que el ejercicio crónico/aeróbico incrementaría mayoritariamente la respiración dependiente de ácidos grasos. A la vista de estos resultados, podemos decir que se produce una respuesta diferenciada en las funciones musculares y su recuperación a los ejercicios anaeróbico y aeróbico. Además, la edad de los ratones afecta el estado de las rutas de señalización de la insulina y el AMPK que se activan con diferente nivel en los ratones viejos y jóvenes. Así, el ejercicio aeróbico indujo el aumento en los animales jóvenes del transporte de la glucosa por GLUT4 mediante las rutas de la insulina y el AMPK, efecto que no se observó tras el ejercicio anaeróbico. En los ratones viejos el transporte de la glucosa por GLUT4 aumentó como consecuencia de la activación de las dos rutas de señalización después de los dos tipos de ejercicio. Los dos tipos de ejercicio activaron la glucólisis independientemente de la edad como un índice de recuperar la necesidad de energía por el músculo esquelético después del ejercicio. Los dos tipos de ejercicio indujeron unas mitocondrias más eficientes mediante el reciclaje mitocondrial, aumento de los complejos mitocondriales, aunque este efecto fue más evidente en el músculo de los ratones viejos después del ejercicio aeróbico/crónico. Además, el ejercicio aeróbico indujo un mayor uso de los ácidos grasos como fuente de energía mientras el ejercicio anaeróbico indujo el uso mayoritario de la glucosa. Es decir, el músculo esquelético de los ratones viejos mostró una mayor demanda de ácidos grasos después del ejercicio aeróbico y una mayor demanda de glucosa después del ejercicio anaeróbico.Universidad Pablo de Olavide. Departamento de Fisiología, Anatomía y Biología CelularPostprin

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

The aging process is characterized by the progressive loss of physiological stability, lower physical and cognitive reserve, and increased vulnerability to death. This progressive deterioration in organismal homeostasis is considered the underlying trigger of most chronic diseases like diabetes, neurodegenerative diseases and cancer. Experimental challenges that increase the rate of biological and cognitive decline are linked to accelerated aging while interventions that slow the aging process are accompanied by an extension in healthy lifespan (López-Otín et al., 2013; Kennedy et al., 2014).This work was supported by the Intramural Research Program of the NIA/NIH.Peer Reviewe

Zinc at the crossroads of exercise and proteostasis

Zinc is an essential element for all forms of life, and one in every ten human proteins is a zinc protein. Zinc has catalytic, structural and signalling functions and its correct homeostasis affects many cellular processes. Zinc deficiency leads to detrimental consequences, especially in tissues with high demand such as skeletal muscle. Zinc cellular homeostasis is tightly regulated by different transport and buffer protein systems. Specifically, in skeletal muscle, zinc has been found to affect myogenesis and muscle regeneration due to its effects on muscle cell activation, proliferation and differentiation. In relation to skeletal muscle, exercise has been shown to modulate zinc serum and urinary levels and could directly affect cellular zinc transport. The oxidative stress induced by exercise may provide the basis for the mild zinc deficiency observed in athletes and could have severe consequences on health and sport performance. Proteostasis is induced during exercise and zinc plays an essential role in several of the associated pathways.This work was supported by the Association Française contre les Myopathies (AFM) through fellowship grant #22450 to C.V.-G., and Spanish Ministry of Education, Culture and Sports [FPU16/03264] for J.D.H.C.Peer reviewe

Relationship between functional capacity and body mass index with plasma coenzyme Q10 and oxidative damage in community-dwelling elderly-people

The impact of aging and physical capacity on coenzyme Q10 (Q10) levels in human blood is unknown. Plasma Q10 is an important factor in cardiovascular diseases. To understand how physical activity in the elderly affects endogenous Q10 levels in blood plasma, we studied a cohort of healthy community-dwelling people. Volunteers were subjected to different tests of the Functional Fitness Test Battery including handgrip strength, six-minute walk, 30 s chair to stand, and time up and go tests. Anthropometric characteristics, plasma Q10 and lipid peroxidation (MDA) levels were determined. Population was divided according to gender and fitness. We found that people showing higher levels of functional capacity presented lower levels of cholesterol and lipid peroxidation accompanied by higher levels of Q10 in plasma. The ratio Q10/cholesterol and Q10/LDL increased in these people. No relationship was found when correlated to muscle strength or agility. On the other hand, obesity was related to lower Q10 and higher MDA levels in plasma affecting women more significantly. Our data demonstrate for the first time that physical activity at advanced age can increase the levels of Q10 and lower the levels of lipid peroxidation in plasma, probably reducing the progression of cardiovascular diseases

Relationship between functional capacity and body mass index with plasma coenzyme Q10 and oxidative damage in community-dwelling elderly-people

The impact of aging and physical capacity on coenzyme Q10 (Q10) levels in human blood is unknown. Plasma Q10 is an important factor in cardiovascular diseases. To understand how physical activity in the elderly affects endogenous Q10 levels in blood plasma, we studied a cohort of healthy community-dwelling people. Volunteers were subjected to different tests of the Functional Fitness Test Battery including handgrip strength, six-minute walk, 30s chair to stand, and time up and go tests. Anthropometric characteristics, plasma Q10 and lipid peroxidation (MDA) levels were determined. Population was divided according to gender and fitness. We found that people showing higher levels of functional capacity presented lower levels of cholesterol and lipid peroxidation accompanied by higher levels of Q10 in plasma. The ratio Q10/cholesterol and Q10/LDL increased in these people. No relationship was found when correlated to muscle strength or agility. On the other hand, obesity was related to lower Q10 and higher MDA levels in plasma affecting women more significantly. Our data demonstrate for the first time that physical activity at advanced age can increase the levels of Q10 and lower the levels of lipid peroxidation in plasma, probably reducing the progression of cardiovascular diseases.the present study was supported by grants from the Government of Andalusia, Spain. The Centro Andaluz de Biología del Desarrollo and Universidad Pablo de Olavide provided human and infrastructure resources funded by Andalusian Government by using FEDER funds (European Commission). Jesús del Pozo-Cruz was awarded a pre-doctoral fellowship funded by the project IMD2010-SC002 from the Centro Andaluz de Medicina del Deporte on behalf of the Government of Andalusia, Spain.Peer Reviewe

Physical activity affects plasma coenzyme Q10 levels differently in young and old humans

Coenzyme Q (Q) is a key lipidic compound for cell bioenergetics and membrane antioxidant activities. It has been shown that also has a central role in the prevention of oxidation of plasma lipoproteins. Q has been associated with the prevention of cholesterol oxidation and several aging-related diseases. However, to date no clear data on the levels of plasma Q during aging are available. We have measured the levels of plasmatic Q10 and cholesterol in young and old individuals showing different degrees of physical activity. Our results indicate that plasma Q10 levels in old people are higher that the levels found in young people. Our analysis also indicates that there is no a relationship between the degree of physical activity and Q10 levels when the general population is studied. However, very interestingly, we have found a different tendency between Q10 levels and physical activity depending on the age of individuals. In young people, higher activity correlates with lower Q10 levels in plasma whereas in older adults this ratio changes and higher activity is related to higher plasma Q10 levels and higher Q10/Chol ratios. Higher Q 10 levels in plasma are related to lower lipoperoxidation and oxidized LDL levels in elderly people. Our results highlight the importance of life habits in the analysis of Q10 in plasma and indicate that the practice of physical activity at old age can improve antioxidant capacity in plasma and help to prevent cardiovascular diseases.This study has been supported by funds from the Andalusian Government as the BIO177 group through FEDER funds (European Commission). The Centro Andaluz de Biología del Desarrollo and the Universidad Pablo de Olavide provided human and infrastructure resources. Jesús del Pozo-Cruz was awarded a pre-doctoral fellowship and the study were funded by the project IMD2010-SC002 from the Centro Andaluz de Medicina del Deporte on behalf of the Government of Andalusia. Tung Bui Thanh received a fellowship from the AECID program (Spanish Ministry of Foreing Affair). ERB, MBS, PN and GLL are also members of the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III.Peer Reviewe

High coenzyme Q10 plasma levels improve stress and damage markers in professional soccer players during competition

Ubiquinol, the reduced form of Coenzyme Q10 (CoQ10), is a key factor in bioenergetics and antioxidant protection. During competition, professional soccer players suffer from considerable physical stress causing high risk of muscle damage. For athletes, supplementation with several antioxidants, including CoQ10, is widely recommended to avoid oxidative stress and muscle damage. We performed an observational study of plasma parameters associated with CoQ10 levels in professional soccer players of the Spanish First League team Athletic Club de Bilbao over two consecutive seasons (n = 24–25) in order determine their relationship with damage, stress and performance during competition. We analyzed three different moments of the competition: preterm, initial phase and mid phase. Metabolites and factors related with stress (testosterone/cortisol) and muscle damage (creatine kinase) were determined. Physical activity during matches was analyzed over the 2015/16 season in those players participating in complete matches. In the mid phase of competition, CoQ10 levels were higher in 2015/16 (906.8 ± 307.9 vs. 584.3 ± 196.3 pmol/mL, p = 0.0006) High levels of CoQ10 in the hardest phase of competition were associated with a reduction in the levels of the muscle-damage marker creatine kinase (Pearsons’ correlation coefficient (r) = − 0.460, p = 0.00168) and a trend for the stress marker cortisol (r = −0.252, p = 0.150). Plasma ubiquinol was also associated with better kidney function (r = −0.287, p = 0.0443 for uric acid). Furthermore, high CoQ10 levels were associated with higher muscle performance during matches. Our results suggest that high levels of plasma CoQ10 can prevent muscle damage, improve kidney function and are associated with higher performance in professional soccer players during competition.This work was supported by 100% Natural, Spain and Kaneka Belgium NV companies that cover the costs of the determinations