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      Exercise-Induced Myokines With Therapeutic Potential for Muscle Wasting

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      Frontiers in Physiology
      Frontiers Media S.A.
      myokines, exercise, exerkines, skeletal muscles, atrophy

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          Abstract

          Skeletal muscle is a highly vascularized tissue that can secrete proteins called myokines. These muscle-secreted factors exert biological functions in muscle itself (autocrine effect) or on short- or long-distant organs (paracrine/endocrine effects) and control processes such as metabolism, angiogenesis, or inflammation. Widely differing diseases ranging from genetic myopathies to cancers are emerging as causing dysregulated secretion of myokines from skeletal muscles. Myokines are also involved in the control of muscle size and may be important to be restored to normal levels to alleviate muscle wasting in various conditions, such as cancer, untreated diabetes, chronic obstructive pulmonary disease, aging, or heart failure. Interestingly, many myokines are induced by exercise (muscle-derived exerkines) and some even by specific types of physical activity, but more studies are needed on this issue. Most exercise-induced myokines travel throughout the body by means of extracellular vesicles. Restoring myokines by physical activity may be added to the list of mechanisms by which exercise exerts preventative or curative effects against a large number of diseases, including the deleterious muscle wasting they may cause. Extending our understanding about which myokines could be usefully restored in certain diseases might help in prescribing more tailored exercise or myokine-based drugs.

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          Most cited references93

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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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            Integrative biology of exercise.

            Exercise represents a major challenge to whole-body homeostasis provoking widespread perturbations in numerous cells, tissues, and organs that are caused by or are a response to the increased metabolic activity of contracting skeletal muscles. To meet this challenge, multiple integrated and often redundant responses operate to blunt the homeostatic threats generated by exercise-induced increases in muscle energy and oxygen demand. The application of molecular techniques to exercise biology has provided greater understanding of the multiplicity and complexity of cellular networks involved in exercise responses, and recent discoveries offer perspectives on the mechanisms by which muscle "communicates" with other organs and mediates the beneficial effects of exercise on health and performance.
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              Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.

              Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                29 March 2019
                2019
                : 10
                : 287
                Affiliations
                Department of Neurosciences, Mario Negri Institute for Pharmacological Research IRCCS , Milan, Italy
                Author notes

                Edited by: Dario Coletti, Sapienza University of Rome, Italy

                Reviewed by: Jennifer Stevenson Moylan, University of Kentucky, United States; Emanuele Berardi, VIB-KU Leuven Center for Cancer Biology, Belgium

                *Correspondence: Rosanna Piccirillo, rosanna.piccirillo@ 123456marionegri.it

                This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2019.00287
                6449478
                30984014
                236bbab8-e4b7-4f0b-9fe3-cbce2f1d69f1
                Copyright © 2019 Piccirillo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 December 2018
                : 04 March 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 115, Pages: 9, Words: 0
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Categories
                Physiology
                Mini Review

                Anatomy & Physiology
                myokines,exercise,exerkines,skeletal muscles,atrophy
                Anatomy & Physiology
                myokines, exercise, exerkines, skeletal muscles, atrophy

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