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      Skeletal muscle: A review of molecular structure and function, in health and disease

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          Abstract

          Decades of research in skeletal muscle physiology have provided multiscale insights into the structural and functional complexity of this important anatomical tissue, designed to accomplish the task of generating contraction, force and movement. Skeletal muscle can be viewed as a biomechanical device with various interacting components including the autonomic nerves for impulse transmission, vasculature for efficient oxygenation, and embedded regulatory and metabolic machinery for maintaining cellular homeostasis. The “omics” revolution has propelled a new era in muscle research, allowing us to discern minute details of molecular cross‐talk required for effective coordination between the myriad interacting components for efficient muscle function. The objective of this review is to provide a systems‐level, comprehensive mapping the molecular mechanisms underlying skeletal muscle structure and function, in health and disease. We begin this review with a focus on molecular mechanisms underlying muscle tissue development (myogenesis), with an emphasis on satellite cells and muscle regeneration. We next review the molecular structure and mechanisms underlying the many structural components of the muscle: neuromuscular junction, sarcomere, cytoskeleton, extracellular matrix, and vasculature surrounding muscle. We highlight aberrant molecular mechanisms and their possible clinical or pathophysiological relevance. We particularly emphasize the impact of environmental stressors (inflammation and oxidative stress) in contributing to muscle pathophysiology including atrophy, hypertrophy, and fibrosis.

          This article is categorized under:

          • Physiology > Mammalian Physiology in Health and Disease

          • Developmental Biology > Developmental Processes in Health and Disease

          • Models of Systems Properties and Processes > Cellular Models

          Abstract

          The current review focuses on molecular structure and function of the various components of muscle physiology. Within each component, we highlight the necessary molecular mechanisms and cross‐talk critical for defining the state of muscle health. We also highlight instances of aberrant molecular mechanisms underlying disease.

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          Most cited references376

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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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            AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

            Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
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              Long non-coding RNAs: new players in cell differentiation and development.

              Genomes of multicellular organisms are characterized by the pervasive expression of different types of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs) belong to a novel heterogeneous class of ncRNAs that includes thousands of different species. lncRNAs have crucial roles in gene expression control during both developmental and differentiation processes, and the number of lncRNA species increases in genomes of developmentally complex organisms, which highlights the importance of RNA-based levels of control in the evolution of multicellular organisms. In this Review, we describe the function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development.
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                Author and article information

                Contributors
                shankar@ucsd.edu
                Journal
                Wiley Interdiscip Rev Syst Biol Med
                Wiley Interdiscip Rev Syst Biol Med
                10.1002/(ISSN)1939-005X
                WSBM
                Wiley Interdisciplinary Reviews. Systems Biology and Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                1939-5094
                1939-005X
                13 August 2019
                Jan-Feb 2020
                : 12
                : 1 ( doiID: 10.1002/wsbm.v12.1 )
                : e1462
                Affiliations
                [ 1 ] Department of Bioengineering University of California San Diego California
                [ 2 ] Department of Bioengineering, Bioinformatics & Systems Biology University of California San Diego California
                [ 3 ] Department of Computer Science and Engineering University of California San Diego California
                [ 4 ] Department of Cellular and Molecular Medicine and Nanoengineering University of California San Diego California
                Author notes
                [*] [* ] Correspondence

                Shankar Subramaniam, Department of Bioengineering, Bioinformatics & Systems Biology, University of California, San Diego, CA.

                Email: shankar@ 123456ucsd.edu

                Author information
                https://orcid.org/0000-0002-3570-2315
                https://orcid.org/0000-0002-8059-4659
                Article
                WSBM1462
                10.1002/wsbm.1462
                6916202
                31407867
                e83cf441-10ae-47ee-a83e-2ff6be39f851
                © 2019 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 April 2019
                : 03 July 2019
                : 03 July 2019
                Page count
                Figures: 16, Tables: 0, Pages: 46, Words: 39472
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: R01 DK109365
                Award ID: R01 HD084633
                Award ID: R01 HL106579
                Award ID: R01 HL108735
                Award ID: R01 LM012595
                Award ID: U01 CA198941
                Award ID: U01 CA200147
                Award ID: U01 DK097430
                Award ID: U19 AI090023
                Award ID: U2C DK119886
                Funded by: National Science Foundation , open-funder-registry 10.13039/100000001;
                Award ID: STC‐0939370
                Categories
                Mammalian Physiology in Health and Disease
                Developmental Processes in Health and Disease
                Cellular Models
                Advanced Review
                Advanced Reviews
                Custom metadata
                2.0
                January/February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.3 mode:remove_FC converted:17.12.2019

                Molecular medicine
                molecular mechanisms,molecular structure,muscle health and disease,muscle physiology,skeletal muscle

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