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      Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

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          Abstract

          Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

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          Most cited references65

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          PGC-1 coactivators: inducible regulators of energy metabolism in health and disease.

          Members of the PPARgamma coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.
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            Skeletal muscle hypertrophy and atrophy signaling pathways.

            Skeletal muscle hypertrophy is defined as an increase in muscle mass, which in the adult animal comes as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. The protein growth factor insulin-like growth factor 1 (IGF-1) has been demonstrated to be sufficient to induce skeletal muscle hypertrophy. Over the past few years, signaling pathways which are activated by IGF-1, and which are responsible for regulating protein synthesis pathways, have been defined. More recently, it has been show that IGF-1 can also block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the ubiquitin-ligases MuRF1 and MAFbx (also called Atrogin-1). Further, it has been demonstrated recently that activation of the NF-kappaB transcription pathway, activated by cachectic factors such as TNFalpha, is sufficient to induce skeletal muscle atrophy, and this atrophy occurs in part via NF-kappaB-mediated upregulation of MuRF1. Further work has demonstrated a trigger for MAFbx expression upon treatment with TNFalpha--the p38 MAPK pathway. This review will focus on the recent progress in the understanding of molecular signalling, which governs skeletal muscle atrophy and hypertrophy, and the known instances of cross-regulation between the two systems.
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              Signaling pathways in skeletal muscle remodeling.

              Skeletal muscle is comprised of heterogeneous muscle fibers that differ in their physiological and metabolic parameters. It is this diversity that enables different muscle groups to provide a variety of functional properties. In response to environmental demands, skeletal muscle remodels by activating signaling pathways to reprogram gene expression to sustain muscle performance. Studies have been performed using exercise, electrical stimulation, transgenic animal models, disease states, and microgravity to show genetic alterations and transitions of muscle fibers in response to functional demands. Various components of calcium-dependent signaling pathways and multiple transcription factors, coactivators and corepressors have been shown to be involved in skeletal muscle remodeling. Understanding the mechanisms involved in modulating skeletal muscle phenotypes can potentiate the development of new therapeutic measures to ameliorate muscular diseases.
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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
                15 November 2019
                November 2019
                : 20
                : 22
                : 5754
                Affiliations
                [1 ]Pasteur Institute, 00161 Rome, Italy; ucci.sara@ 123456gmail.com (S.U.); vale-russi@ 123456hotmail.it (V.R.); claudiamangialardo@ 123456tiscali.it (C.M.); ileniacammarata89@ 123456gmail.com (I.C.); cecilia.vergafalzacappa@ 123456uniroma1.it (C.V.-F.)
                [2 ]DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, 00161 Rome, Italy; alessandra.renzini@ 123456uniroma1.it (A.R.); cavioli.1703739@ 123456studenti.uniroma1.it (G.C.); sergio.adamo@ 123456uniroma1.it (S.A.)
                [3 ]Department of Medico-Surgical Sciences and Biotechnologies Sapienza University of Rome, 04100 Latina, Italy; mariagiulia.santaguida@ 123456uniroma1.it (M.G.S.); camilla.virili@ 123456uniroma1.it (C.V.); marco.centanni@ 123456uniroma1.it (M.C.)
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-4199-2240
                https://orcid.org/0000-0003-0661-1649
                https://orcid.org/0000-0002-1409-0452
                https://orcid.org/0000-0003-1912-0339
                Article
                ijms-20-05754
                10.3390/ijms20225754
                6888244
                31731814
                52fd3f71-ed2a-4b93-bf31-c7fd98b18d53
                © 2019 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
                : 14 October 2019
                : 12 November 2019
                Categories
                Article

                Molecular biology
                muscle atrophy,metabolic reprogramming,thyroid hormone
                Molecular biology
                muscle atrophy, metabolic reprogramming, thyroid hormone

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