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      The age-related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans

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          Highlights

          • Loss of muscle mass with age is due to atrophy and loss of individual muscle fibres.

          • Anabolic resistance is fundamental in age-related fibre atrophy.

          • Fibre loss is associated with denervation and remodelling of motor units.

          • The plasticity of both factors should be considered in future research.

          Abstract

          Age-related loss of skeletal muscle mass and function, sarcopenia, is associated with physical frailty and increased risk of morbidity (chronic diseases), in addition to all-cause mortality. The loss of muscle mass occurs incipiently from middle-age (∼1%/year), and in severe instances can lead to a loss of ∼50% by the 8–9th decade of life. This review will focus on muscle deterioration with ageing and highlight the two underpinning mechanisms regulating declines in muscle mass and function: muscle fibre atrophy and muscle fibre loss (hypoplasia) – and their measurement. The mechanisms of muscle fibre atrophy in humans relate to imbalances in muscle protein synthesis (MPS) and breakdown (MPB); however, since there is limited evidence for basal alterations in muscle protein turnover, it would appear that “anabolic resistance” to fundamental environmental cues regulating diurnal muscle homeostasis (namely physical activity and nutrition), underlie age-related catabolic perturbations in muscle proteostasis. While the ‘upstream’ drivers of the desensitization of aged muscle to anabolic stimuli are poorly defined, they most likely relate to impaired efficiency of the conversion of nutritional/exercise stimuli into signalling impacting mRNA translation and proteolysis. Additionally, loss of muscle fibres has been shown in cadaveric studies using anatomical fibre counts, and from iEMG studies demonstrating motor unit loss, albeit with few molecular investigations of this in humans. We suggest that defining countermeasures against sarcopenia requires improved understandings of the co-ordinated regulation of muscle fibre atrophy and fibre loss, which are likely to be inextricably linked.

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          Most cited references90

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          Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise.

          We hypothesized that an acute bout of strenuous, non-damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n = 8 and 6) of healthy young men were studied over 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload (W(max)). To label tissue proteins in muscle and tendon primed, constant infusions of [1-(13)C]leucine or [1-(13)C]valine and flooding doses of [(15)N] or [(13)C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h(-1)), muscle collagen (0.054% h(-1)), myofibrillar protein (0.121% h(-1)), and sarcoplasmic protein (0.134% h(-1))). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF-I and IGF binding proteins (IGFBP-3 and IGFBP-4) or procollagen type I N-terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.
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            Two weeks of reduced activity decreases leg lean mass and induces "anabolic resistance" of myofibrillar protein synthesis in healthy elderly.

            Alterations in muscle protein metabolism underlie age-related muscle atrophy. During periods of muscle disuse, muscle protein synthesis is blunted, and muscle atrophy occurs in young and old. The impact of a short reduction in physical activity on muscle protein metabolism in older adults is unknown. The aim of this study was to investigate the impact of 14 days of reduced daily steps on fasted and fed-state rates of myofibrillar protein synthesis (MPS) to provide insight into the mechanisms for changes in muscle mass and markers of metabolic health. Before and after 14 days of reduced daily step-count, 10 healthy older adults (age, 72 ± 1 y) underwent measures of insulin sensitivity, muscle strength, physical function, and body composition. Using a primed constant infusion of L-[ring-(13)C6]phenylalanine with serial muscle biopsies, basal, postabsorptive, and postprandial rates of MPS were determined before and after the 14-day intervention. Daily step-count was reduced by approximately 76% to 1413 ± 110 steps per day. Leg fat-free mass was reduced by approximately 3.9% (P < .001). Postabsorptive insulin resistance was increased by approximately 12%, and postprandial insulin sensitivity was reduced by approximately 43% after step reduction (P < .005). Concentrations of TNF-α and C-reactive protein were increased by approximately 12 and 25%, respectively, after step reduction (P < .05). Postprandial rates of MPS were reduced by approximately 26% after the intervention (P = .028), with no difference in postabsorptive rates. The present study demonstrates that 14 days of reduced steps in older adults induces small but measurable reductions in muscle mass that appear to be underpinned by reductions in postprandial MPS and are accompanied by impairments in insulin sensitivity and systemic inflammatory markers and postprandial MPS.
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              Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting.

              The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia.
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                Author and article information

                Contributors
                Journal
                Ageing Res Rev
                Ageing Res. Rev
                Ageing Research Reviews
                Elsevier Science
                1568-1637
                1872-9649
                1 November 2018
                November 2018
                : 47
                : 123-132
                Affiliations
                [0005]MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute of Health Research, Biomedical Research Centre, School of Medicine, University of Nottingham, UK
                Author notes
                [* ]Corresponding author at: MRC-ARUK Centre for Musculoskeletal Ageing Research and National Institute of Health Research, NIHR Biomedical Research Centre, School of Medicine, Derby, DE22 3DT, UK. philip.atherton@ 123456nottingham.ac.uk
                Article
                S1568-1637(18)30134-X
                10.1016/j.arr.2018.07.005
                6202460
                30048806
                fabe7f7b-cdb1-46b6-9a83-671d410606c6
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 May 2018
                : 20 June 2018
                : 18 July 2018
                Categories
                Article

                muscle,atrophy,hypoplasia,anabolic resistance,denervation,sarcopenia

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