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      Satellite Cells and Markers of Muscle Regeneration during Unloading and Reloading: Effects of Treatment with Resveratrol and Curcumin

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          Abstract

          We hypothesized that treatment with pharmacological agents known to increase sirtuin-1 activity (resveratrol and curcumin) may enhance muscle regeneration. In limb muscles of mice (C57BL/6J, 10 weeks) exposed to reloading for seven days following a seven-day period of hindlimb immobilization with/without curcumin or resveratrol treatment, progenitor muscle cell numbers (FACS), satellite cell subtypes (histology), early and late muscle regeneration markers, phenotype and morphometry, sirtuin-1 activity and content, and muscle function were assessed. Treatment with either resveratrol or curcumin in immobilized muscles elicited a significant improvement in numbers of progenitor, activated, quiescent, and total counts of muscle satellite cells, compared to non-treated animals. Treatment with either resveratrol or curcumin in reloaded muscles compared to non-treated mice induced a significant improvement in the CSA of both hybrid (curcumin) and fast-twitch fibers (resveratrol), sirtuin-1 activity (curcumin), sirtuin-1 content (resveratrol), and counts of progenitor muscle cells (resveratrol). Treatment with the pharmacological agents resveratrol and curcumin enhanced the numbers of satellite cells (muscle progenitor, quiescent, activated, and total satellite cells) in the unloaded limb muscles but not in the reloaded muscles. These findings have potential clinical implications as treatment with these phenolic compounds would predominantly be indicated during disuse muscle atrophy to enhance the muscle regeneration process.

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          The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells.

          Stem cells undergo a shift in metabolic substrate utilization during specification and/or differentiation, a process that has been termed metabolic reprogramming. Here, we report that during the transition from quiescence to proliferation, skeletal muscle stem cells experience a metabolic switch from fatty acid oxidation to glycolysis. This reprogramming of cellular metabolism decreases intracellular NAD(+) levels and the activity of the histone deacetylase SIRT1, leading to elevated H4K16 acetylation and activation of muscle gene transcription. Selective genetic ablation of the SIRT1 deacetylase domain in skeletal muscle results in increased H4K16 acetylation and deregulated activation of the myogenic program in SCs. Moreover, mice with muscle-specific inactivation of the SIRT1 deacetylase domain display reduced myofiber size, impaired muscle regeneration, and derepression of muscle developmental genes. Overall, these findings reveal how metabolic cues can be mechanistically translated into epigenetic modifications that regulate skeletal muscle stem cell biology.
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            Substantial skeletal muscle loss occurs during only 5 days of disuse.

            The impact of disuse on the loss of skeletal muscle mass and strength has been well documented. Given that most studies have investigated muscle atrophy after more than 2 weeks of disuse, few data are available on the impact of shorter periods of disuse. We assessed the impact of 5 and 14 days of disuse on skeletal muscle mass, strength and associated intramuscular molecular signalling responses. Twenty-four healthy, young (23 ± 1 year) males were subjected to either 5 (n = 12) or 14 (n = 12) days of one-legged knee immobilization using a full leg cast. Before and immediately after the immobilization period, quadriceps muscle cross-sectional area (CSA), leg lean mass and muscle strength were assessed, and biopsies were collected from the vastus lateralis. Quadriceps muscle CSA declined from baseline by 3.5 ± 0.5 (P < 0.0001) and 8.4 ± 2.8% (P < 0.001), leg lean mass was reduced by 1.4 ± 0.7 (P = 0.07) and 3.1 ± 0.7% (P < 0.01) and strength was decreased by 9.0 ± 2.3 (P < 0.0001) and 22.9 ± 2.6% (P < 0.001) following 5 and 14 days of immobilization respectively. Muscle myostatin mRNA expression doubled following immobilization (P < 0.05) in both groups, while the myostatin precursor isoform protein content decreased after 14 days only (P < 0.05). Muscle MAFBx mRNA expression increased from baseline by a similar magnitude following either 5 or 14 days of disuse, whereas MuRF1 mRNA expression had increased significantly only after 5 days. We conclude that even short periods of muscle disuse can cause substantial loss of skeletal muscle mass and strength and are accompanied by an early catabolic molecular signalling response. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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              Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle.

              Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                23 June 2020
                June 2020
                : 12
                : 6
                : 1870
                Affiliations
                [1 ]Pulmonology Department-Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer Research Group, IMIM-Hospital del Mar, Parc de Salut Mar, Health and Experimental Sciences Department (CEXS), Universitat Pompeu Fabra (UPF), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain; laura.manas@ 123456upf.edu (L.M.-G.); mguitart@ 123456imim.es (M.G.)
                [2 ]Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), 08003 Barcelona, Spain
                [3 ]Scientific and Technical Department, Hospital del Mar-IMIM, 08003 Barcelona, Spain; xduran@ 123456imim.es
                Author notes
                [* ]Correspondence: ebarreiro@ 123456imim.es ; Tel.: +34-93-316-0385; Fax: +34-93-316-0410
                Article
                nutrients-12-01870
                10.3390/nu12061870
                7353305
                32585875
                34d13419-dbcd-47a6-b4ed-2e75e581e22e
                © 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
                : 29 April 2020
                : 18 June 2020
                Categories
                Article

                Nutrition & Dietetics
                muscle unloading,muscle reloading,sirtuin-1,muscle progenitor cells,activated satellite cells,quiescent satellite cells,muscle regeneration markers

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