Research Project: Nutrition, Sarcopenia, Physical Function, and Skeletal Muscle Capacity During Aging

Location: Jean Mayer Human Nutrition Research Center On Aging

2020 Annual Report

Objectives
Objective 1: Characterize the mechanisms associated with nutritional and exercise-related mediators of anabolic resistance associated with sarcopenia, advancing age, and/or reduced mobility in cell/animal models and humans. Sub-objective 1A: Characterize the role of plasticity-related micro-RNA (PR-miRNA) on the anabolic response to specific amino acids, growth factors, and mechanical stretch in skeletal muscle and to further understand the interaction of adipocyte-derived micro-RNA on skeletal muscle anabolic capacity. Sub-objective 1B: Characterize in an exploratory manner the association between gut microbiome composition and function with skeletal muscle composition and performance. Objective 2: Determine the mechanisms by which selected nutrients and/or varying modes of exercise/physical activity influence skeletal muscle performance, cognitive performance, physical functioning, and quality of life in older adults. Sub-objective 2A: Characterize the effects of exercise training on skeletal muscle alone or in combination with daily supplementation of '-3 fatty acids in older adults with mobility limitations and chronic low-grade inflammation. Sub-objective 2B: Characterize the safety, scalability and relative suitability of a low-cost physical activity interventions in older adults with motoric cognitive risk syndrome in a community setting.

Approach
Sarcopenia, the age-associated loss in skeletal muscle mass and function, is a contributing factor to the observed declines in physiological capacity, reduced functional performance, and increased disability and mortality observed with advancing age. The underlying causes of sarcopenia are multi-factorial but include poor nutritional status, reduced levels of physical activity, inflammation, chronic disease burden and other co-morbidities. This project will continue to use a translational science approach to examine the underlying mechanisms by which nutrition and exercise alter skeletal muscle function, and to identify and evaluate the impact of nutritional and exercise interventions on skeletal muscle performance capacity and their potential to prevent or reverse impaired motor/cognitive performance and/or physical dysfunction in older adults. Specifically, we will continue to interrogate skeletal muscle-derived microRNA and microRNA expressed from adipocytes to understand their role in age-related changes in skeletal muscle gene expression and resultant impact on muscle anabolic capacity. In addition, we will investigate the role of age-related alterations in the gut microbiome on skeletal muscle composition and function. We will evaluate the interactive effects of exercise and omega-3 fatty acids on skeletal muscle composition and function in older adults at risk for mobility disability. Finally, we will evaluate the safety and scalability of a community-based exercise intervention in older adults with cognitive and physical limitations. The pairing of basic approaches that identify the molecular landscape and skeletal muscle targets with clinical studies of nutrition and physical activity on sarcopenia will accelerate our ability to translate these findings to aging people.

Progress Report
Our project has made initial progress on both objectives outlined in our plan. In the current project year, we have fully met all of our approved milestones. Work on Objective 1 (Characterize the mechanisms associated with nutritional and exercise-related mediators of anabolic resistance associated with sarcopenia, advancing age, and/or reduced mobility in cell/animal models and humans) and Objective 2 (Determine the mechanisms by which selected nutrients and/or varying modes of exercise/physical activity influence skeletal muscle performance, cognitive performance, physical functioning, and quality of life in older adults) have been initiated. Substantial progress has been made on Objective 1 with recent work illustrating age-related differences in adipose-tissue derived microRNA (miRNA) from aging mice (publication in preparation). miRNA are small non-coding RNA molecules that can modulate gene expression in cells. Some miRNA are secreted by fat cells (adipocytes) and can have effects on other cells such as muscle cells. While the majority of miRNAs in the circulation originate from adipocytes, it is unknown whether our previous observations of decreases in circulating Mirc1 (a family of related miRNAs) with age are due to decreases in its expression within adipocytes. To determine how age impacts adipose tissue miRNA expression, we measured 754 rodent miRNA species in the white (gonadal) adipose tissue of young (6 month) and aged (24 month) C57BL/6J mice. Remarkably, we found significant decreases in 10 members of Mirc1miRNA family in aged vs. young adipose tissue. We then validated the expression of specific Mirc1 members in adipose tissue and exosomes isolated from the adipose tissue in the 6 month and 24 month mice using a more sensitive technique. This analysis confirmed the miRNA screening profiles demonstrating marked decreases in the expression of Mirc1 members in adipocytes from older mice. Moreover, we demonstrated that exosomes (a small vesicle that can transport miRNA) released from adipose tissue after 16 hours in vitro incubation mirrored this expression pattern, with adipose-derived exosomes from 24 MO mice having significantly lower levels of Mirc1 members, compared to exosomes from 6 month mice. These results indicate that the content of adipose-derived miRNA is dramatically altered with age – even in the absence of changes in adiposity. Decreased adipose Mirc1 expression was associated with reduced grip strength, and a severely blunted anabolic response to muscle contraction (high-frequency electrical stimulation [HFES]) in 24 month, compared to 6 month mice. Thus, our results from mice recapitulate relationships were identified in humans: that reduced Mirc1 expression in circulation is predictive of age and anabolic resistance in skeletal muscle. Moreover, our results support the hypothesis that the decline in circulating Mirc1 with age may be attributed to age-associated changes in adipose tissue expression. For Objective 2, the proposed clinical trial designed to examine the safety and scalability of a low-cost physical activity intervention in older adults with motoric cognitive risk syndrome has been initiated. We are conducting a 6-month community-based randomized parallel-group controlled trial to further examine and characterize the effectiveness of translating physical activity into the community among 40 older adults with Motoric Cognitive Risk (MCR). Recruitment and randomizations were conducted and the trial was proceeding smoothly until the COVID-19 pandemic resulted in early discontinuation of the study intervention in currently enrolled participants.

Accomplishments
1. Healthy gut microbes increase muscle strength in the elderly. ARS-funded researchers in Boston, Massachusetts, compared the gut microbiome composition in 18 older adults in good physical condition with 11 older adults in poor physical functioning and observed differences in gut bacteria in the high-functioning older people. They transferred the fecal samples from humans into mice. They confirmed that the gut microbiome older adult microbiome-free mice and found the mice receiving fecal transplants from the high- functioning humans had significantly greater muscle strength than mice receiving fecal transplants from the low-functioning humans. These results suggest a role between the gut microbe and the maintenance of muscle strength with advancing age and may lead to advances in greater mobility and independence for older adults.

Review Publications
Lustgarten, M. 2019. The role of the gut microbiome on skeletal muscle mass and physical function: 2019 update. Frontiers in Physiology. https://doi.org/10.3389/fphys.2019.01435.
Rivas, D., Rice, N., Ezzyat, Y., McDonald, D.J., Cooper, B.E., Fielding, R.A. 2019. Sphingosine-1-phosphate analog FTY720 reverses obesity but not age-induced anabolic resistance to muscle contraction. American Journal of Physiology - Cell Physiology. 317:C502-C512. https://doi.org/10.1152/ajpcell.00455.2018.
Jazani, N.H., Savoj, J., Lustgarten, M., Lau, W., Vaziri, N.D. 2019. Impact of gut dysbiosis on neurohormonal pathways in chronic kidney disease. Diseases. 7(1):21. https://doi.org/10.3390/diseases7010021.
Aversa, Z., Zhang, X., Fielding, R.A., Lanza, I., Lebrasseur, N.K. 2019. The clinical impact and biological mechanisms of skeletal muscle aging. Bone. 127:26-36. https://doi.org/10.1016/j.bone.2019.05.021.
Beaudart, C., Rolland, Y., Cruz-Jentoft, A.J., Bauer, J.M., Sieber, C., Cooper, C., Al-Daghri, N., Araujo De Carvalho, I., Bautmans, I., Bernabei, R., Bruyere, O., Cesari, M., Cherubini, A., Dawson-Hughes, B., Kanis, J.A., Kaufman, J., Landi, F., Maggi, S., McCloskey, E., Petermans, J., Rodriguez Manas, L., Reginster, J., Roller-Wirnsberger, R., Schaap, L.A., Uebelhart, D., Rizzoli, R., Fielding, R.A. 2019. Assessment of muscle function and physical performance in daily clinical practice: a position paper endorsed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Muscoloskeletal Diseases (ESCEO). Calcified Tissue International. 105(1):1-14. https://doi.org/10.1007/s00223-019-00545-w.
Bauer, J.M., Cruz-Jentoft, A.J., Fielding, R.A., Kanis, J.A., Reginster, J., Bruyere, O., Cesari, M., Chapurlat, R., Al-Daghri, N., Dennison, E., Kaufman, J., Landi, F., Laslop, A., Locquet, M., Maggi, S., Mccloskey, E., Perna, S., Rizzoli, R., Rolland, Y., Rondanelli, M., Szulc, P., Vellas, B., Vlaskovska, M., Cooper, C. 2019. Is there enough evidence for osteosarcopenic obesity as a distinct entity? A critical literature review. Calcified Tissue International. 105(2):109-124. https://doi.org/10.1007/s00223-019-00561-w.
Reid, K.F., Bannuru, R.R., Wang, C., Mori, D.L., Niles, B.L. 2019. The effects of tai chi mind-body approach on the mechanisms of gulf war illness: an umbrella review. Integrative Medicine Research. 8(3):167-172. https://doi.org/10.1016/j.imr.2019.05.003.
Westbury, L.D., Syddall, H.E., Fuggle, N.R., Dennison, E.M., Cauley, J.A., Shiroma, E.J., Fielding, R.A., Newman, A.B., Cooper, C. 2020. Long term rates of change in musculoskeletal aging and body composition: findings from the Health, Aging and Body Composition Study. Calcified Tissue International. https://doi.org/10.1007/s00223-020-00679-2.
Glynn, N.W., Gmelin, T., Santanasto, A.J., Lovato, L.C., Lange-Maia, B.S., Nicklas, B.J., Fielding, R.A., Manini, T.M., Myers, V.H., De Rekeneire, N., Spring, B.J., Pahor, M., King, A.C., Rejeski, W., Newman, A.B. 2019. Impact of baseline fatigue on a physical ability intervention to prevent mobility disability. Journal of the American Geriatrics Society. https://doi.org/10.1111/jgs.16274.
Savikangas, T., Tirkkonen, A., Alen, M., Rantanen, T., Fielding, R.A., Rantalainen, T., Sipila, S. 2020. Associations of physical activity in detailed intensity ranges with body composition and physical function. a cross-sectional study among sedentary older adults. European Review of Aging and Physical Activity. 17:4. https://doi.org/10.1186/s11556-020-0237-y.
Brown, J.D., Smith, S.M., Strotmeyer, E.S., Kritchevsky, S.B., Gill, T.M., Blair, S.N., Fielding, R.A., Buford, T.W., Pahor, M., Manini, T.M. 2019. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on response to a physical activity intervention in older adults: results from the Lifestyle Interventions for Elders study. Journals of Gerontology. https://doi.org/10.1093/gerona/glz120.
Grosicki, G.J., Englund, D.A., Price, L.L., Iwai, M., Kashiwa, M., Reid, K.F., Fielding, R.A. 2019. Lower-extremity torque capacity and physical function in mobility-limited older adults. Journal of Nutrition Health and Aging. 23:703-709. https://doi.org/10.1007/s12603-019-1232-8.
Orwig, D., Magaziner, J., Fielding, R.A., Zhu, H., Binder, E.F., Cawthon, P., Bhasin, S., Correa-De-Araujo, R., Manini, T., Patel, S., Shardell, M., Travison, T.G. 2020. Application of SDOC cut points for low muscle strength for recovery of walking speed after hip fracture. Journal of Gerontology Medical Science. 75(7):1379-1385. https://doi.org/10.1093/gerona/glaa076.
Grosicki, G.J., Barrett, B.B., Englund, D.A., Liu, C., Travison, T.G., Cederholm, T., Koochek, A., Von Berens, A., Gustafsson, T., Benard, T., Reid, K.F., Fielding, R.A. 2019. Circulating interleukin-6 is associated with skeletal muscle strength, quality, and functional adaptation with exercise training in mobility-limited older adults. The Journal of Frailty and Aging. 9:57-63. https://doi.org/10.14283/jfa.2019.30.
Fielding, R.A., Reeves, A.R., Jasuja, R., Liu, C., Barrett, B.B., Lustgarten, M.S. 2019. Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults. Experimental Gerontology. 127. https://doi.org/10.1016/j.exger.2019.110722.
Rodriguez-Manas, L., Araujo De Carvalho, I., Bhasin, S., Bischoff-Ferrara, H.A., Cesari, M., Evans, W., Hare, J.M., Pahor, M., Parini, A., Rolland, Y., Fielding, R.A., Watson, J., Vellas, B. 2019. ICFSR task force perspective on biomarkers for sarcopenia and frailty. The Journal of Frailty and Aging. 9(1):4-8. https://doi.org/10.14283/jfa.2019.32.