Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling

2013 ◽  
Vol 114 (9) ◽  
pp. 1329-1339 ◽  
Author(s):  
N. A. Pansters ◽  
R. C. Langen ◽  
E. F. Wouters ◽  
A. M. Schols
Keyword(s):  
Clinical Trial ◽  
Protein Synthesis ◽  
Protein Expression ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Anabolic Steroids ◽  
Specific Gene ◽  
Muscle Recovery ◽  
Igf I ◽  
The Impact

Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

scholarly journals From reporters to endogenous genes: the impact of the first five codons on translation efficiency in Escherichia coli

2019 ◽  
Author(s):  
Mariana H. Moreira ◽  
Géssica C. Barros ◽  
Rodrigo D. Requião ◽  
Silvana Rossetto ◽  
Tatiana Domitrovic ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Synthesis ◽  
Protein Expression ◽  
Nucleotide Composition ◽  
Control Mechanisms ◽  
Translation Efficiency ◽  
Coding Region ◽  
E Coli ◽  
Endogenous Proteins ◽  
The Impact

ABSTRACTTranslation initiation is a critical step in the regulation of protein synthesis, and it is subjected to different control mechanisms, such as 5’ UTR secondary structure and initiation codon context, that can influence the rates at which initiation and consequentially translation occur. For some genes, translation elongation also affects the rate of protein synthesis. With a GFP library containing nearly all possible combinations of nucleotides from the 3rd to the 5th codon positions in the protein coding region of the mRNA, it was previously demonstrated that some nucleotide combinations increased GFP expression up to four orders of magnitude. While it is clear that the codon region from positions 3 to 5 can influence protein expression levels of artificial constructs, its impact on endogenous proteins is still unknown. Through bioinformatics analysis, we identified the nucleotide combinations of the GFP library in Escherichia coli genes and examined the correlation between the expected levels of translation according to the GFP data with the experimental measures of protein expression. We observed that E. coli genes were enriched with the nucleotide compositions that enhanced protein expression in the GFP library, but surprisingly, it seemed to affect the translation efficiency only marginally. Nevertheless, our data indicate that different enterobacteria present similar nucleotide composition enrichment as E. coli, suggesting an evolutionary pressure towards the conservation of short translational enhancer sequences.

scholarly journals Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

2017 ◽  
Vol 122 (5) ◽  
pp. 1336-1350 ◽  
Author(s):  
Leslie M. Baehr ◽  
Daniel W. D. West ◽  
Andrea G. Marshall ◽  
George R. Marcotte ◽  
Keith Baar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Hindlimb Unloading ◽  
Medial Gastrocnemius ◽  
Old Rats ◽  
The Impact

Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (−9 to −38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy.

scholarly journals Skeletal Muscle Recovery from Disuse Atrophy: Protein Turnover Signaling and Strategies for Accelerating Muscle Regrowth

2020 ◽  
Vol 21 (21) ◽  
pp. 7940
Author(s):  
Timur M. Mirzoev
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Mechanical Loading ◽  
Protein Turnover ◽  
Skeletal Muscle Mass ◽  
Molecular Mechanisms ◽  
Muscle Protein ◽  
Muscle Recovery ◽  
Mechanical Unloading

Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle mass (muscle atrophy). The maintenance of skeletal muscle mass is dependent on the balance between rates of muscle protein synthesis and breakdown. While molecular mechanisms regulating protein synthesis during mechanical unloading have been relatively well studied, signaling events implicated in protein turnover during skeletal muscle recovery from unloading are poorly defined. A better understanding of the molecular events that underpin muscle mass recovery following disuse-induced atrophy is of significant importance for both clinical and space medicine. This review focuses on the molecular mechanisms that may be involved in the activation of protein synthesis and subsequent restoration of muscle mass after a period of mechanical unloading. In addition, the efficiency of strategies proposed to improve muscle protein gain during recovery is also discussed.

scholarly journals Effects of a Novel Selective Androgen Receptor Modulator on Dexamethasone-Induced and Hypogonadism-Induced Muscle Atrophy

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3706-3719 ◽  
Author(s):  
Amanda Jones ◽  
Dong-Jin Hwang ◽  
Ramesh Narayanan ◽  
Duane D. Miller ◽  
James T. Dalton
Keyword(s):  
Protein Synthesis ◽  
Androgen Receptor ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Testosterone Propionate ◽  
Levator Ani ◽  
Ubiquitin Ligases ◽  
Selective Androgen Receptor Modulator ◽  
Receptor Modulator ◽  
Igf I

Glucocorticoids are the most widely used antiinflammatory drugs in the world. However, prolonged use of glucocorticoids results in undesirable side effects such as muscle wasting, osteoporosis, and diabetes. Skeletal muscle wasting, which currently has no approved therapy, is a debilitating condition resulting from either reduced muscle protein synthesis or increased degradation. The imbalance in protein synthesis could occur from increased expression and function of muscle-specific ubiquitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1), or decreased function of the IGF-I and phosphatidylinositol-3 kinase/Akt kinase pathways. We examined the effects of a nonsteroidal tissue selective androgen receptor modulator (SARM) and testosterone on glucocorticoid-induced muscle atrophy and castration-induced muscle atrophy. The SARM and testosterone propionate blocked the dexamethasone-induced dephosphorylation of Akt and other proteins involved in protein synthesis, including Forkhead box O (FoxO). Dexamethasone caused a significant up-regulation in the expression of ubiquitin ligases, but testosterone propionate and SARM administration blocked this effect by phosphorylating FoxO. Castration induced rapid myopathy of the levator ani muscle, accompanied by up-regulation of MAFbx and MuRF1 and down-regulation of IGF-I, all of which was attenuated by a SARM. The results suggest that levator ani atrophy caused by hypogonadism may be the result of loss of IGF-I stimulation, whereas that caused by glucocorticoid treatment relies almost solely on up-regulation of MAFbx and MuRF1. Our studies provide the first evidence that glucocorticoid- and hypogonadism-induced muscle atrophy are mediated by distinct but overlapping mechanisms and that SARMs may provide a more effective and selective pharmacological approach to prevent glucocorticoid-induced muscle loss than steroidal androgen therapy.

Resistance exercise and nutrition to counteract muscle wasting

2009 ◽  
Vol 34 (5) ◽  
pp. 817-828 ◽  
Author(s):  
Jonathan P. Little ◽  
Stuart M. Phillips
Keyword(s):  
Protein Synthesis ◽  
Resistance Exercise ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Effective Means ◽  
Resistance Exercise Training ◽  
Highly Effective

Loss of muscle mass is an unfavourable consequence of aging and many chronic diseases. The debilitating effects of muscle loss include declines in physical function and quality of life and increases in morbidity and mortality. Loss of muscle mass is the result of a decrease in muscle protein synthesis, an increase in muscle protein degradation, or a combination of both. Much research on muscle wasting has tended to focus on preventing muscle protein breakdown, and less attention has been paid to providing adequate stimulation to increase muscle protein synthesis. In this review, we present evidence to suggest that interventions aimed at increasing muscle protein synthesis represent the most effective countermeasure for preventing, delaying, or reversing the loss of skeletal muscle mass experienced in various muscle wasting conditions. Based on results from acute and chronic studies in humans in a wide variety of wasting conditions, we propose that resistance exercise training combined with appropriately timed protein (likely leucine-rich) ingestion represents a highly effective means to promote muscle hypertrophy, and may represent a highly effective treatment strategy to counteract the muscle wasting tassociated with aging and chronic disease.

scholarly journals Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

2017 ◽  
Vol 44 (1) ◽  
pp. 267-278 ◽  
Author(s):  
Britta Wåhlin-Larsson ◽  
Daniel J. Wilkinson ◽  
Emelie Strandberg ◽  
Adrian Hosford-Donovan ◽  
Philip J. Atherton ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Mass ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Inflammatory Marker ◽  
Immunofluorescent Staining ◽  
Age Related ◽  
Human Myotubes ◽  
The Impact ◽  
The Relationship

Background/Aims: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro. Methods: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67±1.7 years). Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting. Results: We observed an inverse relationship between circulating CRP level and muscle mass (β= -0.646 (95% CI: -0.888, -0.405) p<0.05) and demonstrated a reduction (p < 0.05) in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05) in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRP-mediated increased phosphorylation (p<0.05) of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-β, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis. Conclusion: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.

scholarly journals Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3101
Author(s):  
Emanuele Rinninella ◽  
Marco Cintoni ◽  
Pauline Raoul ◽  
Carmelo Pozzo ◽  
Antonia Strippoli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Nutritional Support ◽  
Muscle Wasting ◽  
Early Recognition ◽  
Clinical Implications ◽  
Molecular Pathways ◽  
Muscle Loss ◽  
Skeletal Muscle Loss ◽  
The Impact

In cancer patients, loss of muscle mass is significantly associated with low tolerability of chemotherapy and poor survival. Despite the great strides in the treatment of cancer, targeted therapies such as tyrosine kinase inhibitors (TKIs) could exacerbate muscle wasting. Over recent years, the impact of skeletal muscle loss during TKI therapy on clinical outcomes has been in the spotlight. In this review, we focus on the different molecular pathways of TKIs potentially involved in muscle wasting. Then, we report the results of the studies assessing the effects of different TKI therapies—such as sorafenib, regorafenib, sunitinib, and lenvatinib—on muscle mass, and highlight their potential clinical implications. Finally, we discuss an integrative nutritional approach to be adopted during TKI treatment. The assessment of muscle mass from computerized tomography imaging could be helpful in predicting toxicity and prognosis in patients treated with TKI such as sorafenib. Early recognition of low muscle mass and effective personalized nutritional support could prevent or attenuate muscle mass wasting. However, the role of nutrition is still overlooked, and future clinical trials are needed to find the optimal nutritional support to countermeasure muscle mass depletion during TKI therapy.

840 Myostatin Deficiency Inhibits Muscle Wasting and Improves Bacterial Clearance and Survival in Septic Mice

2020 ◽  
Vol 41 (Supplement_1) ◽  
pp. S259-S260
Author(s):  
Masao Kaneki ◽  
Masayuki Kobayashi ◽  
Shingo Kasamatsu ◽  
Shingo Yasuhara ◽  
Shohei Shinozaki
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Wasting ◽  
Burn Injury ◽  
Bacterial Load ◽  
Bacterial Clearance ◽  
Liver And Kidney

Abstract Introduction Sepsis is a leading cause of the mortality of burn patients. Muscle wasting is a major complication of sepsis and burn injury and negatively affects clinical outcomes of patients with sepsis and burn injury. Myostatin (MSTN) is a myokine that causes muscle atrophy by activating the activin type 2 receptor (ActRII) pathway and myostatin deficiency increases skeletal muscle mass. However, a role of myostatin in critical illness (e.g., sepsis, burn injury)-induced muscle wasting has not yet been investigated. Moreover, a role of muscle wasting in immune suppression and mortality in sepsis is unknown. Methods Sepsis was induced by cecum ligation and puncture (CLP) in male MSTN-deficient mice at 8 weeks of age and age- and body weight (BW)-matched wild type (WT) mice. Survival was monitored for 14 days. Bacterial clearance was evaluated at 16 h after CLP by measuring bacterial load in the peritoneal cavity and circulation. The weight of gastrocnemius (GC), tibialis anterior (TA) and soleus (SOL) muscle and cross-sectional areas of GC were measured before and at 14 days after CLP. To evaluate neutrophil organ infiltration, myeloperoxidase (MPO) activity was measured in the liver and kidney at 16 h after CLP. To evaluate liver dysfunction, acute kidney injury and inflammatory response, plasma levels of AST, ALT, NGAL and high mobility group box 1 (HMGB1) were measured at 16 h after CLP. Protein expression of Murf-1 and Atrogin-1, key players in muscle wasting, and ActRIIB was evaluated in GC muscle by immunoblotting at 3 days and 16 h after CLP, respectively. Results MSTN deficiency increased skeletal muscle mass and inhibited sepsis-induced muscle wasting compared with BW-matched WT mice. Sepsis-induced increase in Murf-1, but not Atrogin-1, expression in muscle was attenuated by MSTN deficiency. CLP increased protein expression of ActRIIB in muscle. Moreover, MSTN deficiency reduced mortality of septic mice compared with age- and BW-matched WT mice. MSTN deficiency improved bacterial clearance and ameliorated increases in MPO activity in the liver and kidney and plasma concentrations of AST, ALT, NGAL and HMGB1 in septic mice. Conclusions Our data showed that MSTN deficiency inhibited muscle wasting and improved bacterial clearance and survival in septic mice. These data indicate that MSTN plays an important role in sepsis-induced muscle wasting. Moreover, our findings suggest that muscle wasting may not be just a complication of sepsis but a driver of sepsis development contributing to mortality of septic mice. This study also raises the possibility that muscle wasting and/or activation of the MSTN-ActRII pathway may exacerbate sepsis-induced immune dysfunction. Applicability of Research to Practice Our study identifies the MSTN-ActRII pathway as a novel, potential molecular target to ameliorate muscle wasting and improve survival of septic burned patients.

scholarly journals Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting

2020 ◽  
Vol 295 (51) ◽  
pp. 17441-17459
Author(s):  
Hawley E. Kunz ◽  
Jessica M. Dorschner ◽  
Taylor E. Berent ◽  
Thomas Meyer ◽  
Xuewei Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Protein ◽  
Coupling Efficiency ◽  
C2c12 Myotubes ◽  
Tumor Bearing

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.

Multiple muscle wasting-related transcription factors are acetylated in dexamethasone-treated muscle cells

2012 ◽  
Vol 90 (2) ◽  
pp. 200-208 ◽  
Author(s):  
Wei Chamberlain ◽  
Patricia Gonnella ◽  
Nima Alamdari ◽  
Zaira Aversa ◽  
Per-Olof Hasselgren
Keyword(s):  
Transcription Factors ◽  
Muscle Mass ◽  
Posttranslational Modifications ◽  
Muscle Wasting ◽  
Muscle Cells ◽  
L6 Myotubes ◽  
Vitro Model ◽  
L6 Muscle Cells ◽  
The Impact

Recent studies suggest that the expression and activity of the histone acetyltransferase p300 are upregulated in catabolic muscle allowing for acetylation of cellular proteins. The function of transcription factors is influenced by posttranslational modifications, including acetylation. It is not known if transcription factors involved in the regulation of muscle mass are acetylated in atrophying muscle. We determined cellular levels of acetylated C/EBPβ, C/EBPδ, FOXO1, FOXO3a, and NF-kB/p65 in dexamethasone-treated L6 muscle cells, a commonly used in vitro model of muscle wasting. The role of p300 in dexamethasone-induced transcription factor acetylation and myotube atrophy was examined by transfecting muscle cells with p300 siRNA. Treatment of L6 myotubes with dexamethasone resulted in increased cellular levels of acetylated C/EBPβ and δ, FOXO1 and 3a, and p65. Downregulation of p300 with p300 siRNA reduced acetylation of transcription factors and decreased dexamethasone-induced myotube atrophy and expression of the ubiquitin ligase MuRF1. The results suggest that several muscle wasting-related transcription factors are acetylated supporting the concept that posttranslational modifications of proteins regulating gene transcription may be involved in the loss of muscle mass. The results also suggest that acetylation of the transcription factors is at least in part regulated by p300 and plays a role in glucocorticoid-induced muscle atrophy. Targeting molecules that regulate acetylation of transcription factors may help reduce the impact of muscle wasting.

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