Molecular assessment of muscle health and function : The effect of age, nutrition and physical activity on the human muscle transcriptome and metabolom
Hangelbroek, Roland W.J. - \ 2017
Wageningen University. Promotor(en): A.H. Kersten; C.P.G.M. de Groot, co-promotor(en): M.V. Boekschoten. - Wageningen : Wageningen University - ISBN 9789463437103 - 205
muscles - age - nutrition - physical activity - transcriptomes - metabolomes - elderly - creatine - phosphocreatine - vitamin d - atrophy - spieren - leeftijd - voeding - lichamelijke activiteit - transcriptomen - metabolomen - ouderen - creatine - fosfocreatine - vitamine d - atrofie
Prolonged lifespan and decreased fertility will lead to an increased proportion of older adults in the world population (population aging). An important strategy to deal with population aging has been to promote healthy aging; not only to prevent mounting health care costs, but also to maintain independence and quality of life of older populations for as long as possible. Close to the opposite of the healthy aging is frailty. A major component of (physical) frailty is sarcopenia: age-related loss of muscle mass. Decreased muscle size and strength has been associated with a wide variety of negative health outcomes, including increased risk of hospitalization, physical disability and even death. Therefore, maintaining muscle size and strength is very important for healthy aging. Nutrition and physical activity are possible strategies to maintain or even improve muscle function with age.
The effect of nutrition, age, frailty and physical activity on the function of skeletal muscle is complex. A better understanding of the molecular mechanisms involved can provide new insights in potential strategies to maintain muscle function over the life course. This thesis aims to investigate these mechanisms and processes that underlie the effects of age, frailty and physical activity by leveraging the sensitivity and comprehensiveness of transcriptomics and metabolomics.
Chapter 2 and 3 describe the effects of age, frailty and resistance-type exercise training on the skeletal muscle transcriptome and metabolome. Both the transcriptome and metabolome show significant differences between frail and healthy older adults. These differences are similar to the differneces between healthy young men and healthy older adults, suggesting that frailty presents itself as a more pronounced form of aging, somewhat independent of chronological age. These age and frailty related differences in the transcriptome are partially reversed by resistance-type exercise training, in accordance with the observed improvement in muscle strength. Regression analysis revealed that the protocadherin gamma gene cluster may be important to skeletal muscle function. Protocadherin gamma is involved in axon guidance and may be upregulated due to the denervation-reinnervation cycles observed in skeletal muscle of older individuals. The metabolome suggested that resistance-type exercise training led to a decrease in branched-chain amino acid oxidation, as shown by a decrease in amino acid derived carnitines. Lastly, the blood metabolome showed little agreement with the metabolome in skeletal muscle, indicating that blood is a poor read-out of muscle metabolism.
We assessed the effect of knee immobilization with creatine supplementation or placebo on the skeletal muscle transcriptome and metabolome in chapter 4. Knee immobilization caused muscle mass loss and strength loss in all participants, with no differences between creatine and placebo groups. Knee immobilization appeared to induce the HDAC4-myogenin axis, which is primarily associated with denervation and motor neuron diseases. The metabolome showed changes consistent with the decreased expression of energy metabolism genes. While acyl-carnitine levels tended to decrease with knee immobilization, one branched-chain amino acid-derived acyl carnitine was increased after knee immobilization, suggesting increased amino acid oxidation.
Vitamin D deficiency is common among older adults and has been linked to muscle weakness. Vitamin D supplementation has been proposed as a strategy to improve muscle function among older populations. In chapter 5, supplementation with vitamin D (calcifediol, 25(OH)D) is investigated as nutritional strategy to improve muscle function among frail older adults. However, we observed no effect of vitamin D on the muscle transcriptome. These findings indicate the effects of vitamin D supplementation on skeletal muscle may be either absent, weak, or limited to a small subset of muscle cells.
Transcriptomic changes due to different forms of muscle disuse are compared in chapter 6 (primarily knee immobilization and bed rest). The goal was to determine the similarities and differences among various causes of muscle atrophy in humans (primarily muscle disuse). Both knee immobilization and bed rest led to significant changes in the muscle transcriptome. However, the overlap in significantly changed genes was relatively small. Knee immobilization was characterized by ubiquitin-mediated proteolysis and induction of the HDAC4/Myogenin axis, whereas bed rest revealed increased expression of genes of the immune system and increased expression of lysosomal genes. Knee immobilization showed the highest similarity with age and frailty-related transcriptomic changes. This finding suggests that knee immobilization may be the most suitable form of disuse atrophy to assess the effectiveness of strategies to prevent age-related muscle loss in humans.
The transcriptome and metabolome are incredibly useful tools in describing the wide array of biological systems within skeletal muscle. These systems can be modulated using physical activity (or lack thereof) as well as nutrition. This thesis describes some of these processes and highlights several unexplored genes and metabolites that may be important for maintaining or even optimizing muscle function. In the future, it may be possible to optimize both exercise and nutrition for each individual using these techniques; or even better, cheaper and less invasive alternatives.
Nutritional interventions to preserve skeletal muscle mass
Backx, Evelien M.P. - \ 2016
Wageningen University. Promotor(en): Lisette de Groot; L.J.C. van Loon. - Wageningen : Wageningen University - ISBN 9789462579149 - 158
musculoskeletal system - nutritional intervention - skeletal muscle - vitamin d - creatine - leucine - nandrolone - protein intake - young adults - elderly - overweight - athletes - preservation - skeletspierstelsel - maatregel op voedingsgebied - skeletspier - vitamine d - creatine - leucine - nandrolon - eiwitinname - jongvolwassenen - ouderen - overgewicht - atleten - behoud
Muscle mass is the main predictor for muscle strength and physical function. The amount of muscle mass can decline rapidly during periods of reduced physical activity or during periods of energy intake restriction. For athletes, it is important to maintain muscle mass, since the loss of muscle is associated with decreased muscle strength, decreased physical performance and a longer recovery period. In the older and more clinically compromised populations, the consequences of muscle loss can substantially impact metabolic health, physical functioning, quality of life and mortality rates. In this thesis, the effects of different nutritional interventions on the preservation of muscle mass are being evaluated.
Vitamin D deficiency (serum 25-hydroxyvitamin D or 25(OH)D) has been associated with increased muscle loss and reduced muscle strength. In chapter 2, we identified seasonal changes in 25(OH)D concentration in elite athletes. We observed that 25(OH)D concentrations were highest at the end of summer (113±26 nmol/L), and lowest at the end of winter (78±30 nmol/L). Athletes that had a sufficient 25(OH)D concentration (>75 nmol/L) at the start of the study, still had a high risk (20%) of being deficient (<50 nmol/L) in late winter. Thus, a sufficient 25(OH)D concentration in summer does not guarantee a sufficient status in winter. In chapter 3, we assessed 25(OH)D concentrations in 128 highly-trained athletes and found that 70% had a deficient or insufficient 25(OH)D concentration at the end of the winter season. Supplementation with 2200 IU/d vitamin D resulted in a sufficient 25(OH)D concentration in 80% of the athletes after 12 months and was therefore a better dosage to improve 25(OH)D concentration than 400 or 1100 IU/d.
In the following chapters, we assessed the effects of creatine supplementation (chapter 4), leucine supplementation (chapter 5) and nandrolone administration (chapter 6) on the preservation of muscle mass during a short period of muscle disuse. For all of these compounds there is prior evidence for their efficacy in augmenting muscle mass and strength gains in combination with resistance-type exercise training and all have been suggested to attenuate the loss of muscle mass during a period of muscle disuse. During 7 days of single-leg immobilization, muscle mass decreased by ~6% and muscle strength decreased by ~8%. Surprisingly, none of the tested compounds attenuated the loss of muscle mass during 7 days of single-leg immobilization in healthy, young men.
In chapter 7, we performed a fully controlled dietary intervention to assess the impact of a high protein intake on the preservation of lean body mass during 12 weeks of energy intake restriction. Sixty-one overweight and obese men and women were randomly assigned to either a high protein diet (1.7 g/kg/d) or a normal protein diet (0.9 g/kg/d) during 12 weeks of 25% energy intake restriction. During the dietary intervention, subjects lost 9±3 kg body weight with a concomitant 2±2 kg decline in lean body mass with no differences between the two intervention groups. Thus, increasing protein intake above habitual intake levels (0.9 g/kg/d) did not preserve lean body mass during a period of energy intake restriction.
Finally, in chapter 8 we reflected on the main findings described in this thesis. In this chapter, we point out that the populations studied were all healthy and well-nourished. We conclude that in these populations, additional creatine, leucine and protein beyond habitual intakes did not preserve muscle mass. Older and/or malnourished individuals might be more responsive to these nutritional interventions. Future research could also focus on the combined effects of two or more nutritional compounds during disuse that are known to affect different mechanisms. Moreover, we speculate that the tested nutritional compounds could be effective in accelerating the regain of muscle mass and strength after a period of muscle loss. However, it should be noted that muscle loss during disuse occurs at a rate that is several-fold greater than muscle (re)gain during resistance type exercise training. Therefore, it is imperative that we continue our endeavors to identify nutritional or pharmaceutical compounds or exercise mimetics that may help to prevent or attenuate disuse atrophy.
|Melkzuur- en creatine- en creatininemetabolisme : een literatuurstudie = Metabolism of lactate and creatine - creatinine : a review
Berende, P.L.M. ; Groot, M.J. - \ 1995
Lelystad : ID-DLO (Rapport / ID-DLO (Lokatie Runderweg) no. 273) - 41
dierfysiologie - vleesvee - kalveren - enzymen - melkzuur - creatine - creatinine - literatuuroverzichten - animal physiology - beef cattle - calves - enzymes - lactic acid - creatine - creatinine - literature reviews
Lactaat- en creatinegehalten en hun verhouding in urine van vleeskalveren, vleesstieren, vleesvaarzen, fokkalveren en melkkoeien : implicaties voor de L/C verhouding als screeningsmethode voor het gebruik van beta-agonisten
Berende, P.L.M. ; Lommen, A. ; Bannink, H. ; Groot, M.J. - \ 1993
Wageningen : DLO-Rijks-Kwaliteitsinstituut voor Land- en Tuinbouwprodukten (Rapport / RIKILT-DLO 93.15) - 13
melkzuur - vleesvee - urine-analyse - creatine - bèta-adrenerge agonisten - screenen - lactic acid - beef cattle - urine analysis - creatine - beta-adrenergic agonists - screening
Ontwikkeling van fysiologische screenings- en monitoringsmethoden via metabolietprofilering met NMR : testonderwerp: urinecompositie van met beta-agonisten behandelde mestkalveren
Lommen, A. ; Huf, F.A. ; Schilt, R. ; Groot, M. ; Berende, P.L.M. - \ 1991
Wageningen : DLO-Rijks-Kwaliteitsinstituut voor Land- en Tuinbouwprodukten (Rapport / RIKILT-DLO 91.56) - 20
urine-analyse - bèta-adrenerge agonisten - metabolieten - kernmagnetische resonantiespectroscopie - kalveren - creatine - melkzuur - urine analysis - beta-adrenergic agonists - metabolites - nuclear magnetic resonance spectroscopy - calves - creatine - lactic acid
In dit onderzoek zijn met behulp van NMR (Nuclear Magnetic Resonance) potentiele parameters (lactaat- en creatine-concentratie) gevonden in mestkalverurine, waarmee in praktijk gescreend kan worden op het gebruik van beta-agonisten.