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.
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.
Our project has made continued progress on both objectives outlined in our plan. In the current project year, we have fully or substantially 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, 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 continued under the pandemic restrictions related to social distancing and capacity limits. 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 is secreted by fat cells (adipocytes) and can affect other cells such as muscle cells. While most 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. We have continued our work on Mirc1. Recently, we questioned whether Mirc1 expression altered myostatin/SMAD signaling in skeletal muscle. Myostatin (MSTN), a member of the transforming growth factor ß (TGFß) superfamily, is a robust inhibitor of skeletal muscle hypertrophy during postnatal development and skeletal muscle mass in adulthood. An increase in myostatin expression is the molecular signature of multiple pathological conditions leading to a loss of muscle mass in experimental and clinical studies. Moreover, genetic or pharmacological inhibition of myostatin has been successfully used to prevent or limit the decrease in skeletal muscle mass occurring in several mouse models of muscle wasting. We have also identified that myostatin action can be inhibited by muscle contraction via phosphorylation of its downstream effector SMAD2, and that this resistance-exercise mediated regulatory event is necessary to induce muscle growth with overload. To determine if Mirc1 can regulate myostatin/SMAD expression, we overexpressed miR-19b in isolated human myocytes, as we found this Mirc1 member to be predictive of anabolic response to exercise in humans. miR-19b was successfully overexpressed in HMCL-7301 human myocytes using an adenoviral construct under the control of a CMV promoter with a GFP reporter. Control cells were transduced with a vector containing beta-Galactosidase (Ad5-beta-gal). Consistent with a role for Mirc1 in myostatin inhibition, we demonstrated that overexpressing miR-19b decreases the expression of MSTN, SMAD2, and SMAD3; and increases the expression of the MSTN inhibitor, SMAD7. Moreover, miR-19b decreased the expression of the myostatin targets, Trim63 and FBX032, which are E3 ligases that promote skeletal muscle atrophy. Importantly, we also found that miR-19b overexpression caused an increase in muscle protein synthesis at baseline and in response to IGF-1 stimulation. Together, these data demonstrate that miR-19b can negatively regulate the expression of MSTN/SMAD pathway members, leading to a reduction of protein degradation pathways and amplified anabolic capacity in human myocytes. For Objective 2, the clinical trial designed to examine the safety and scalability of a low-cost physical activity intervention in older adults with Motoric Cognitive Risk syndrome was suspended and completed early. MCR is a recently defined pre-dementia syndrome characterized by slow walking speeds and subjective memory complaints. MCR avoids the need for complex neuropsychological testing, yet its assessment can robustly identify older persons who have a substantially greater risk of developing subsequent dementia. The feasibility of lifestyle interventions for maintaining or improving outcomes in MCR has not been examined. To address this knowledge gap, we initiated a translational randomized controlled trial (RCT) of 24-weeks of physical activity (PA) or a healthy aging education (HE) control intervention in an urban senior center in Greater Boston. A total of 79 older adults attended the senior center for a screening visit, of whom 29 met the MCR criteria and were deemed eligible for participation. Twenty-five participants with MCR (age: 74.4 ± 7 yrs; BMI: 32.4 ± 7 kg/m2; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1 m/sec) were randomized and 13 participants had completed PA (n = 6) or HE (n = 7). Participants successfully adhered to the study interventions (attendance rate: PA: 69.3% vs. HE:70.1%), and no study-related adverse events occurred in PA or HE. This study provides important information for the design of larger-scale RCTs to preserve the independence of vulnerable older adults with MCR in community-based settings.
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Cawthon, P.M., Manini, T., Patel, S.M., Newman, A., Travison, T., Kiel, D.P., Santanasto, A.J., Ensrud, K.E., Xue, Q., Shardell, M., Duchowny, K., Erlandson, K.M., Pencina, K.M., Fielding, R.A., Magaziner, J., Kwok, T., Karlsson, M., Ohlsson, C., Mellstrom, D., Hirani, V., Ribom, E., Correa-De-Araujo, R., Bhasin, S. 2020. Putative cut-points in sarcopenia components and incident adverse health outcomes: an SDOC analysis. Journal of the American Geriatrics Society. 68:1429-1437. https://doi.org/10.1111/jgs.16517.
Westbury, L.D., Syddall, H.E., Fuggle, N.R., Dennison, E.M., Harvey, N.C., Cauley, J.A., Shiroma, E.J., Fielding, R., Newman, A.B., Cooper, C. 2020. Relationships between level and change in sarcopenia and other body composition components and adverse health outcomes: findings from the health, aging, and body composition study. Calcified Tissues International. 108:302-313. https://doi.org/10.1007/s00223-020-00775-3.
Patel, S.M., Duchowny, K.A., Kiel, D.P., Correa-de-Araujo, R., Fielding, R.A., Travison, T., Magaziner, J., Manini, T., Xue, Q., Newman, A.B., Pencina, K.M., Santanasto, A., Bhasin, S., Cawthon, P.M. 2020. Sarcopenia definition & outcomes consortium defined low grip strength in two cross-sectional, population-based cohorts. Journal of the American Geriatrics Society. https://doi.org/10.1111/jgs.16419.
Harvey, N.C., Orwoll, E., Kwok, T., Karlsson, M.K., Rosengren, B.E., Ribom, E., Cauley, J.A., Cawthon, P.M., Ensrud, K., Liu, E., Cruz-Jentoft, A.J., Fielding, R.A., Cooper, C., Kanis, J.A., Lorentzon, M., Ohlsson, C., Mellstrom, D., Johansson, H., Mccloskey, E. 2021. Sarcopenia definitions as predictors of fracture risk independent of FRAX, falls, and BMD in the osteoporotic fractures in men (MrOS) study: a meta-analysis. Journal of Bone and Mineral Research. 36(7):1235-1244. https://doi.org/10.1002/JBMR.4293.
Bhasin, S., Travison, T.G., Manini, T.M., Patel, S., Pencina, K.M., Fielding, R.A., Magaziner, J.M., Newman, A.B., Kiel, D.P., Cooper, C., Guralnik, J.M., Cauley, J.A., Arai, H., Clark, B.C., Landi, F., Schaap, L.A., Pereira, S.L., Rooks, D., Woo, J., Woodhouse, L.J., Binder, E., Brown, T., Shardell, M., Xue, Q., D'Agostino Sr., R.B., Orwig, D., Grosicki, G., Correa-de-Araujo, R., Cawthon, P.M. 2020. Sarcopenia definition: The position statements of the sarcopenia definition and outcomes consortium. Journal of the American Geriatrics Society. 68:1410-1418. https://doi.org/10.1111/jgs.16372.
Beavers, D.P., Kritchevsky, S.B., Gill, T.M., Ambrosius, W.T., Anton, S.D., Fielding, R.A., King, A.C., Rejeski, W., Lovato, L., McDermott, M.M., Newman, A.B., Pahor, M., Walkup, M.P., Tracy, R.P., Manini, T.M. 2021. Elevated IL-6 and CRP levels are associated with incident self-reported major mobility disability: A pooled analysis of older adults with slow gait speed. Journals of Gerontology. https://doi.org/10.1093/gerona/glab093.
Reginster, J., Beaudart, C., Al-Daghri, N., Avouac, B., Bauer, J., Bere, N., Bruyere, O., Cerreta, F., Cesari, M., Rosa, M., Cooper, C., Cruz Jentoft, A.J., Dennison, E., Geerinck, A., Gielen, E., Landi, F., Laslop, A., Maggi, S., Concepcion Prieto, Y., Rizzoli, R., Sundseth, H., Sieber, C., Trombetti, A., Vellas, B., Veronese, N., Visser, M., Vlaskovska, M., Fielding, R.A. 2020. Update on the ESCEO recommendation for the conduct of clinical trials for drugs aiming at the treatment of sarcopenia in older adults. Aging Clinical Experimental Research. https://doi.org/10.1007/s40520-020-01663-4.
Custodero, C., Anton, S.D., Beavers, D.P., Mankowski, R.T., Lee, S.A., McDermott, M.M., Fielding, R.A., Newman, A.B., Tracy, R.P., Kritchevsky, S.B., Ambrosius, W.T., Pahor, M., Manini, T.M. 2020. The relationship between interleukin-6 levels and physical performance in mobility-limited older adults with chronic low-grade inflammation: the ENRGISE pilot study. Archives of Gerontology and Geriatrics. 90. Article 104131. https://doi.org/10.1016/j.archger.2020.104131.