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Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.

ABSTRACT: BACKGROUND:Glucocorticoids (GC) play a major role in muscle atrophy. As skeletal muscle is a secretory organ, characterization of the muscle secretome elicited by muscle atrophy should allow to better understand the cellular mechanisms and to identify circulating biomarkers of this condition. Our project aimed to identify the changes in the muscle secretome associated with GC-induced muscle atrophy and susceptible to translate into circulation. METHODS:We have identified the GC-induced changes in the secretome of C2 C12 muscle cells by proteomic analysis, and then, we have determined how these changes translate into the circulation of mice or human subjects exposed to high concentrations of GC. RESULTS:This approach led us to identify Serpina3n as one of the most markedly secreted protein in response to GC. Our original in vitro results were confirmed in vivo by an increased expression of Serpina3n in skeletal muscle (3.9-fold; P < 0.01) and in the serum (two-fold; P < 0.01) of mice treated with GC. We also observed increased levels of the human orthologue Serpina3 in the serum of Cushing's syndrome patients compared with healthy controls matched for age and sex (n = 9/group, 2.5-fold; P < 0.01). An increase of Serpina3n was also demonstrated in muscle atrophy models mediated by GC such as cancer cachexia (four-fold; P < 0.01), sepsis (12.5-fold; P < 0.001), or diabetes (two-fold; P < 0.01). In contrast, levels of Serpina3n both in skeletal muscle and in the circulation were reduced in several models of muscle hypertrophy induced by myostatin inhibition (P < 0.01). Furthermore, a cluster of data suggests that the regulation of muscle Serpina3n involves mTOR, an essential determinant of the muscle cell size. CONCLUSIONS:Taken together, these data suggest that Serpina3n may represent a circulating biomarker of muscle atrophy associated to GC and, broadly, a reflection of dynamic changes in muscle mass.

SUBMITTER: Gueugneau M

PROVIDER: S-EPMC6204594 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.

Gueugneau Marine M d'Hose Donatienne D Barbé Caroline C de Barsy Marie M Lause Pascale P Maiter Dominique D Bindels Laure B LB Delzenne Nathalie M NM Schaeffer Laurent L Gangloff Yann-Gaël YG Chambon Christophe C Coudy-Gandilhon Cécile C Béchet Daniel D Thissen Jean-Paul JP

Journal of cachexia, sarcopenia and muscle 20180710 5

<h4>Background</h4>Glucocorticoids (GC) play a major role in muscle atrophy. As skeletal muscle is a secretory organ, characterization of the muscle secretome elicited by muscle atrophy should allow to better understand the cellular mechanisms and to identify circulating biomarkers of this condition. Our project aimed to identify the changes in the muscle secretome associated with GC-induced muscle atrophy and susceptible to translate into circulation.<h4>Methods</h4>We have identified the GC-in ...[more]

PMID: 29989354

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Project description:BackgroundMuscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds.MethodsFor in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake.ResultsIn Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells.ConclusionsThese findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.

Dataset Information

Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.

Publications

Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.

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