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      Inactivity and Skeletal Muscle Metabolism: A Vicious Cycle in Old Age

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          Abstract

          Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers, as well as medical professionals, there are many challenges yet to be solved in order to counteract the effects of aging on muscle function efficiently. Noteworthy, it has been shown that aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a number of predisposing (risk) factors such as telomere attrition, epigenetic changes, mitochondrial dysfunction, sedentary behavior (leading to body composition alterations), age-related low-grade systemic inflammation (inflammaging), hormonal imbalance, as well as a hypoproteic diet (unable to counterbalance the repercussions of the age-related increase in skeletal muscle catabolism). The present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the modifications in skeletal muscle metabolism associated with aging and physical activity.

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          Muscles, exercise and obesity: skeletal muscle as a secretory organ.

          During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
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            Inflammaging and 'Garb-aging'.

            'Inflammaging' refers to the chronic, low-grade inflammation that characterizes aging. Inflammaging is macrophage centered, involves several tissues and organs, including the gut microbiota, and is characterized by a complex balance between pro- and anti-inflammatory responses. Based on literature data, we argue that the major source of inflammatory stimuli is represented by endogenous/self, misplaced, or altered molecules resulting from damaged and/or dead cells and organelles (cell debris), recognized by receptors of the innate immune system. While their production is physiological and increases with age, their disposal by the proteasome via autophagy and/or mitophagy progressively declines. This 'autoreactive/autoimmune' process fuels the onset or progression of chronic diseases that can accelerate and propagate the aging process locally and systemically. Consequently, inflammaging can be considered a major target for antiaging strategies.
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              Epigenetic Predictor of Age

              From the moment of conception, we begin to age. A decay of cellular structures, gene regulation, and DNA sequence ages cells and organisms. DNA methylation patterns change with increasing age and contribute to age related disease. Here we identify 88 sites in or near 80 genes for which the degree of cytosine methylation is significantly correlated with age in saliva of 34 male identical twin pairs between 21 and 55 years of age. Furthermore, we validated sites in the promoters of three genes and replicated our results in a general population sample of 31 males and 29 females between 18 and 70 years of age. The methylation of three sites—in the promoters of the EDARADD, TOM1L1, and NPTX2 genes—is linear with age over a range of five decades. Using just two cytosines from these loci, we built a regression model that explained 73% of the variance in age, and is able to predict the age of an individual with an average accuracy of 5.2 years. In forensic science, such a model could estimate the age of a person, based on a biological sample alone. Furthermore, a measurement of relevant sites in the genome could be a tool in routine medical screening to predict the risk of age-related diseases and to tailor interventions based on the epigenetic bio-age instead of the chronological age.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                16 January 2020
                January 2020
                : 21
                : 2
                : 592
                Affiliations
                [1 ]Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania; elena.rezus@ 123456umfiasi.ro (E.R.); anca.cardoneanu@ 123456umfiasi.ro (A.C.)
                [2 ]Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania; ciprian.rezus@ 123456umfiasi.ro
                [3 ]Center for Rheumatic Diseases, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; catalin.codreanu@ 123456reumatologiedrstoia.ro
                [4 ]Department of Rheumatology and Physiotherapy,“George Emil Palade” University of Medicine, Pharmacy, Science and Technology, 540139 Târgu Mureş, Romania; mirela.parvu@ 123456umfst.ro
                [5 ]Department of Pharmacology, Clinical Pharmacology and Algesiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania; rusu.i.gabriela@ 123456umfiasi.ro
                [6 ]Advanced Center for Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700454 Iaşi, Romania; bogdan.tamba@ 123456umfiasi.ro
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-7361-4685
                https://orcid.org/0000-0001-9868-1999
                Article
                ijms-21-00592
                10.3390/ijms21020592
                7014434
                31963330
                4fcd4f42-5a51-497c-abea-2fed446996b7
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 November 2019
                : 07 January 2020
                Categories
                Review

                Molecular biology
                aging,sarcopenia,muscle mitochondria,catabolism,anabolism,inflammation,adipokine,myokine,sedentary lifestyle,exercise

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