scholarly journals Drosophila Activin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes

2020 ◽  
Author(s):  
Myung-Jun Kim ◽  
Michael B. O’Connor
Keyword(s):  
Muscle Growth ◽  
Muscle Cells ◽  
Negative Regulator ◽  
Muscle Size ◽  
Mammalian Skeletal Muscle ◽  
Wild Type ◽  
Activin Signaling ◽  
Sarcomeric Protein ◽  
Muscle Geometry ◽  
Tgfβ Superfamily

SummaryThe Myostatin/Activin branch of the TGFβ superfamily acts as a negative regulator of mammalian skeletal muscle size, in part, through downregulation of insulin/IGF-1 signaling. Surprisingly, recent studies in Drosophila indicate that Activin signaling acts as a positive regulator of muscle size. Here we demonstrate that Drosophila Activin signaling promotes growth of the muscle cells along all three axes; width, length and thickness. In addition, Activin signaling positively regulates the InR/dTORC1 pathway and the level of MHC, an essential sarcomeric protein, via promoting the transcription of Pdk1 and Akt1. Enhancing InR/dTORC1 signaling in the muscle of Activin pathway mutants restores MHC levels close to wild-type, but only increased the width of muscle cells. In contrast, hyperactivation of the Activin pathway increases the length of muscle cells even when MHC levels were lowered by suppression of dTORC1. Together, these results indicate that Drosophila Activin pathway regulates larval muscle geometry via promoting InR/dTORC1-dependent MHC production and the differential assembly of sarcomeric components into either pre-existing (width) or new (length) sarcomeric units depending on the balance of InR/dTORC1 and Activin signals.

scholarly journals Drosophila Activin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes

Development ◽  
2020 ◽  
pp. dev.190868
Author(s):  
Myung-Jun Kim ◽  
Michael B. O'Connor
Keyword(s):  
Muscle Growth ◽  
Negative Regulator ◽  
Muscle Size ◽  
Wild Type ◽  
Larval Body ◽  
Activin Signaling ◽  
Sarcomeric Protein ◽  
Muscle Geometry ◽  
Tgfβ Superfamily ◽  
Vertebrate Skeletal Muscle

The Myostatin/Activin branch of the TGFβ superfamily acts as a negative regulator of vertebrate skeletal muscle size, in part, through downregulation of insulin/IGF-1 signaling. Surprisingly, recent studies in Drosophila indicate that motoneuron derived Activin signaling acts as a positive regulator of muscle size. Here we demonstrate that Drosophila Activin signaling promotes growth of the muscle cells along all three axes; width, thickness and length. Activin signaling positively regulates the InR/dTORC1 pathway and the level of Mhc, an essential sarcomeric protein, via increased Pdk1 and Akt1 expression. Enhancing InR/dTORC1 signaling in the muscle of Activin pathway mutants restores Mhc levels close to wild-type, but only increases muscle width. In contrast, hyperactivation of the Activin pathway in muscles increases overall larval body and muscle fiber length even when Mhc levels were lowered by suppression of dTORC1. Together, these results indicate that the Drosophila Activin pathway regulates larval muscle geometry and body size via promoting InR/dTORC1-dependent Mhc production and the differential assembly of sarcomeric components into either pre-existing or new sarcomeric units depending on the balance of InR/dTORC1 and Activin signals.

Pharmacological Inhibition of Myostatin and Changes in Lean Body Mass and Lower Extremity Muscle Size in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

2014 ◽  
Vol 99 (10) ◽  
pp. E1967-E1975 ◽  
Author(s):  
Desmond Padhi ◽  
Celestia S. Higano ◽  
Neal D. Shore ◽  
Paul Sieber ◽  
Erik Rasmussen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lean Body Mass ◽  
Body Mass ◽  
Phase 1 ◽  
Muscle Growth ◽  
Androgen Deprivation ◽  
Negative Regulator ◽  
Muscle Size ◽  
Muscle Loss ◽  
Lower Extremity Muscle

Abstract Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat, and currently available therapies have limited efficacy to treat this complication. The antimyostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective of the study was to evaluate the safety, pharmacokinetics, and muscle efficacy of AMG 745 in men undergoing ADT for nonmetastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled, multiple-dose, phase 1 study of AMG 745 given for 28 days. The end point of percentage change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry was prespecified. Results: Rates of adverse events (AMG 745 vs placebo) were the following: diarrhea (13% vs 9%), fatigue (13% vs 4%), contusion (10% vs 0%), and injection site bruising (6% vs 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg vs the placebo groups on day 29 by 2.2% (±0.8% SE, P = 0.008); in exploratory fat mass analysis, a decrease of −2.5% (±1.0% SE, P = 0.021) was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after day 29. Conclusion: Four weekly sc doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for nonmetastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.

scholarly journals Myostatin-1 Inhibits Cell Proliferation by Inhibiting the mTOR Signal Pathway and MRFs, and Activating the Ubiquitin-Proteasomal System in Skeletal Muscle Cells of Japanese Flounder Paralichthys olivaceus

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2376
Author(s):  
Jiahuan Liu ◽  
Mingzhu Pan ◽  
Dong Huang ◽  
Yanlin Guo ◽  
Mengxi Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Mrna Expression ◽  
Biological Effects ◽  
Paralichthys Olivaceus ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Signal Pathway ◽  
Japanese Flounder ◽  
Negative Regulator

Myostatin (MSTN) is a negative regulator of skeletal muscle growth and development. The mechanisms of fish MSTN involved in muscle growth are not fully understood. In the present study, knockdown and overexpression of mstn-1 was performed in cultured Japanese flounder muscle cells to investigate the molecular function and the underlying mechanism of fish MSTN-1. Results showed that mstn-1 knockdown significantly induced cell proliferation and the mRNA expression of myogenic regulatory factors (MRFs), while overexpression of mstn-1 led to a significant decrease of cell proliferation and a suppression of the MRFs mRNA expression. The overexpression of mstn-1 also significantly increased the mRNA expression of ubiquitin–proteasomal pathway of proteolysis genes including muscle RING-finger protein 1 (murf-1) by 204.1% (p = 0.024) and muscle atrophy F-box protein (mafbx) by 165.7% (p = 0.011). However, mystn-1 overexpression inhibited the activation of mTOR signal pathway and the AKT/FoxO1 pathway through decreasing phosphorylation of AKT at Ser 473 by 56.0% (p = 0.001). Meanwhile, mystn-1 overexpression increased the dephosphorylation and nuclear localization of FoxO1 by 394.9% (p = 0.005). These results demonstrate that mstn-1 in Japanese flounder has the effects of inhibiting cell proliferation and growth, and the mTOR and AKT/FoxO1 pathways participated in these biological effects.

Abstract 355: Increasing Muscle Mass Improves Vascular Function In Obese Mice

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Shuiqing Qiu ◽  
James Mintz ◽  
Christina Salet ◽  
Nitirut Nernpermpisooth ◽  
David Fulton ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Vascular Function ◽  
Muscle Growth ◽  
Gluteus Maximus ◽  
Mesenteric Arteries ◽  
Negative Regulator ◽  
Muscle Size ◽  
Obese Mice ◽  
Fiber Size ◽  
Oxide Synthase

Exercise improves endothelial function in obese patients. Salutatory effects of exercise include increases in muscle size and quality, reduction in fat mass and alterations of the plasma milieu. The relationships between these changes and improvements in vascular function are poorly defined. Hypothesis Increasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice. Myostatin deletion increased muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%, triceps 57.64%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%, triceps 103.61%). Myostatin deletion increased muscle fiber size in lean and obese mice (p< 0.05) but had no significant effects on adipocyte size in obese mice. Fasting glucose, HbA1c and glucose tolerance were improved in obese myostatin null mice. Obese mice demonstrated superoxide-mediated impairment of ACh-induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved ACh-induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L-NAME. PGI 2 and EDHF mediated vasodilation were preserved in obese mice, and unaffected by myostatin deletion. Treatment with sepiapterin (a precursor of the nitric oxide synthase cofactor tetrahydrobiopoterin) restored impairment of vasodilation in obese mice, and this improvement was blocked by L-NAME. Taken together, these data suggested that increasing muscle mass by deletion of myostatin improved NO not PGI 2 or EDHF mediated vasodilation in obese mice.

scholarly journals Marker-assisted introgression of the Compact mutant myostatin allele MstnCmpt-dl1Abc into a mouse line with extreme growth effects on body composition and muscularity

2004 ◽  
Vol 84 (3) ◽  
pp. 161-173 ◽  
Author(s):  
LUTZ BÜNGER ◽  
GERHARD OTT ◽  
LÁSZLÓ VARGA ◽  
WERNER SCHLOTE ◽  
CHARLOTTE REHFELDT ◽  
...  
Keyword(s):  
Body Fat ◽  
Muscle Growth ◽  
Segregation Ratio ◽  
Quadriceps Muscle ◽  
Negative Regulator ◽  
Wild Type ◽  
Fat Depots ◽  
Total Body Fat ◽  
Gene Expression Studies ◽  
Total Body

Myostatin is a negative regulator of muscle growth and mutations in its gene lead to muscular hypertrophy and reduced fat. In cattle, this is seen in ‘double muscled’ breeds. We have used marker-assisted introgression to introduce a murine myostatin mutation, MstnCmpt-dl1Abc [Compact (C)], into an inbred line of mice (DUHi) that had been selected on body weight and had exceptional growth. Compared with homozygous wild-type mice, homozygous (C/C) mice of this line were ~4–5% lighter, had ~7–8% shorter tails, substantially increased muscle weights (e.g. quadriceps muscle in males was 59% heavier) and an increased ‘dressing percentage’ (~49% vs 39%), an indicator of overall muscularity. The weights of several organs (e.g. liver, kidney, heart and digestive tract) were significantly reduced, by 12–20%. Myostatin deficiency also resulted in drastic reductions of total body fat and of various fat depots, total body fat proportion falling from ~17·5% in wild-type animals of both sexes to 9·5% and 11·6% in homozygous (C/C) females and males, respectively. Males with a deficiency in myostatin had higher gains in muscle traits than females. Additionally, there was a strong distortion of the segregation ratio on the DUHi background. Of 838 genotyped pups from inter se matings 29%, 63% and 8% were homozygous wild type (+/+), heterozygous (C/+) and homozygous (C/C), respectively, showing that MstnCmpt-dl1Abc has lower fitness on this background. This line, when congenic, will be a useful resource in gene expression studies and for finding modifying genes.

scholarly journals Regulation of the Growth of Multinucleated Muscle Cells by an Nfatc2-Dependent Pathway

2001 ◽  
Vol 153 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Valerie Horsley ◽  
Bret B. Friday ◽  
Sarah Matteson ◽  
Kristy Miller Kegley ◽  
Jonathan Gephart ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Muscle Size ◽  
Growth Defect ◽  
Activated T Cells ◽  
Cross Sectional ◽  
Development And Differentiation ◽  
Muscle Cultures

The nuclear factor of activated T cells (NFAT) family of transcription factors regulates the development and differentiation of several tissue types. Here, we examine the role of NFATC2 in skeletal muscle by analyzing adult NFATC2−/− mice. These mice exhibit reduced muscle size due to a decrease in myofiber cross-sectional area, suggesting that growth is blunted. Muscle growth was examined during regeneration after injury, wherein NFATC2-null myofibers form normally but display impaired growth. The growth defect is intrinsic to muscle cells, since the lack of NFATC2 in primary muscle cultures results in reduced cell size and myonuclear number in myotubes. Retroviral-mediated expression of NFATC2 in the mutant cells rescues this cellular phenotype. Myonuclear number is similarly decreased in NFATC2−/− mice. Taken together, these results implicate a novel role for NFATC2 in skeletal muscle growth. We demonstrate that during growth of multinucleated muscle cells, myoblasts initially fuse to form myotubes with a limited number of nuclei and that subsequent nuclear addition and increases in myotube size are controlled by a molecular pathway regulated by NFATC2.

scholarly journals Myostatin propeptide mutation of the hypermuscular Compact mice decreases the formation of myostatin and improves insulin sensitivity

2017 ◽  
Vol 312 (3) ◽  
pp. E150-E160 ◽  
Author(s):  
Tamas Kocsis ◽  
Gyorgy Trencsenyi ◽  
Kitti Szabo ◽  
Julia Aliz Baan ◽  
Geza Muller ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Genetic Background ◽  
Negative Regulator ◽  
Metabolic Effects ◽  
Muscle Size ◽  
Whole Body ◽  
Rab Gtpase ◽  
Wild Type ◽  
Absolute Size

The TGFβ family member myostatin (growth/differentiation factor-8) is a negative regulator of skeletal muscle growth. The hypermuscular Compact mice carry the 12-bp Mstn(Cmpt-dl1Abc) deletion in the sequence encoding the propeptide region of the precursor promyostatin, and additional modifier genes of the Compact genetic background contribute to determine the full expression of the phenotype. In this study, by using mice strains carrying mutant or wild-type myostatin alleles with the Compact genetic background and nonmutant myostatin with the wild-type background, we studied separately the effect of the Mstn(Cmpt-dl1Abc) mutation or the Compact genetic background on morphology, metabolism, and signaling. We show that both the Compact myostatin mutation and Compact genetic background account for determination of skeletal muscle size. Despite the increased musculature of Compacts, the absolute size of heart and kidney is not influenced by myostatin mutation; however, the Compact genetic background increases them. Both Compact myostatin and genetic background exhibit systemic metabolic effects. The Compact mutation decreases adiposity and improves whole body glucose uptake, insulin sensitivity, and 18FDG uptake of skeletal muscle and white adipose tissue, whereas the Compact genetic background has the opposite effect. Importantly, the mutation does not prevent the formation of mature myostatin; however, a decrease in myostatin level was observed, leading to altered activation of Smad2, Smad1/5/8, and Akt, and an increased level of p-AS160, a Rab-GTPase-activating protein responsible for GLUT4 translocation. Based on our analysis, the Compact genetic background strengthens the effect of myostatin mutation on muscle mass, but those can compensate for each other when systemic metabolic effects are compared.

scholarly journals Time-resolved transcriptional profiling of Trichinella-infected murine myocytes helps to elucidate host–pathogen interactions in the muscle stage

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xiaoxiang Hu ◽  
Xiaolei Liu ◽  
Chen Li ◽  
Yulu Zhang ◽  
Chengyao Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Biology ◽  
Trichinella Spiralis ◽  
Expression Patterns ◽  
Muscle Cells ◽  
Host Cells ◽  
Initial Reaction ◽  
Global Changes ◽  
Mammalian Skeletal Muscle ◽  
Time Resolved

Abstract Background Parasites of the genus Trichinella are the pathogenic agents of trichinellosis, which is a widespread and severe foodborne parasitic disease. Trichinella spiralis resides primarily in mammalian skeletal muscle cells. After invading the cells of the host organism, T. spiralis must elude or invalidate the host’s innate and adaptive immune responses to survive. It is necessary to characterize the pathogenesis of trichinellosis to help to prevent the occurrence and further progression of this disease. The aims of this study were to elucidate the mechanisms of nurse cell formation, pathogenesis and immune evasion of T. spiralis, to provide valuable information for further research investigating the basic cell biology of Trichinella-infected muscle cells and the interaction between T. spiralis and its host. Methods We performed transcriptome profiling by RNA sequencing to identify global changes at 1, 3, 7, 10 and 15 days post-infection (dpi) in gene expression in the diaphragm after the parasite entered and persisted within the murine myocytes; the mice were infected by intravenous injection of newborn larvae. Gene expression analysis was based on the alignment results. Differentially expressed genes (DEGs) were identified based on their expression levels in various samples, and functional annotation and enrichment analysis were performed. Results The most extensive and dynamic gene expression responses in host diaphragms were observed during early infection (1 dpi). The number of DEGs and genes annotated in the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases decreased significantly in the infected mice compared to the uninfected mice at 3 and 7 dpi, suddenly increased sharply at 10 dpi, and then decreased to a lower level at 15 dpi, similar to that observed at 3 and 7 dpi. The massive initial reaction of the murine muscle cells to Trichinella infection steadied in the later stages of infection, with little additional changes detected for the remaining duration of the studied process. Although there were hundreds of DEGs at each time point, only 11 genes were consistently up- or downregulated at all 5 time points. Conclusions The gene expression patterns identified in this study can be employed to characterize the coordinated response of T. spiralis-infected myocytes in a time-resolved manner. This comprehensive dataset presents a distinct and sensitive picture of the interaction between host and parasite during intracellular infection, which can help to elucidate how pathogens evade host defenses and coordinate the biological functions of host cells to survive in the mammalian environment.

scholarly journals Effects of temperature on proliferation of myoblasts from donor piglets with different thermoregulatory maturities

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Katharina Metzger ◽  
Dirk Dannenberger ◽  
Armin Tuchscherer ◽  
Siriluck Ponsuksili ◽  
Claudia Kalbe
Keyword(s):  
Muscle Development ◽  
Muscle Growth ◽  
Extreme Temperature ◽  
Growth Inhibitor ◽  
Muscle Cells ◽  
The Body ◽  
Farm Animals ◽  
Neonatal Piglets ◽  
Protein Levels

Abstract Background Climate change and the associated risk for the occurrence of extreme temperature events or permanent changes in ambient temperature are important in the husbandry of farm animals. The aim of our study was to investigate the effects of permanent cultivation temperatures below (35 °C) and above (39 °C, 41 °C) the standard cultivation temperature (37 °C) on porcine muscle development. Therefore, we used our porcine primary muscle cell culture derived from satellite cells as an in vitro model. Neonatal piglets have limited thermoregulatory stability, and several days after birth are required to maintain their body temperature. To consider this developmental step, we used myoblasts originating from thermolabile (five days of age) and thermostable piglets (twenty days of age). Results The efficiency of myoblast proliferation using real-time monitoring via electrical impedance was comparable at all temperatures with no difference in the cell index, slope or doubling time. Both temperatures of 37 °C and 39 °C led to similar biochemical growth properties and cell viability. Only differences in the mRNA expression of myogenesis-associated genes were found at 39 °C compared to 37 °C with less MYF5, MYOD and MSTN and more MYH3 mRNA. Myoblasts grown at 35 °C are smaller, exhibit higher DNA synthesis and express higher amounts of the satellite cell marker PAX7, muscle growth inhibitor MSTN and metabolic coactivator PPARGC1A. Only permanent cultivation at 41 °C resulted in higher HSP expression at the mRNA and protein levels. Interactions between the temperature and donor age showed that MYOD, MYOG, MYH3 and SMPX mRNAs were temperature-dependently expressed in myoblasts of thermolabile but not thermostable piglets. Conclusions We conclude that 37 °C to 39 °C is the best physiological temperature range for adequate porcine myoblast development. Corresponding to the body temperatures of piglets, it is therefore possible to culture primary muscle cells at 39 °C. Only the highest temperature of 41 °C acts as a thermal stressor for myoblasts with increased HSP expression, but it also accelerates myogenic development. Cultivation at 35 °C, however, leads to less differentiated myoblasts with distinct thermogenetic activity. The adaptive behavior of derived primary muscle cells to different cultivation temperatures seems to be determined by the thermoregulatory stability of the donor piglets.

Transcriptomic Analysis of MSTN Knockout in the Early Differentiation of Chicken Fetal Myoblasts

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 58
Author(s):  
Ke Xu ◽  
Hao Zhou ◽  
Chengxiao Han ◽  
Zhong Xu ◽  
Jinmei Ding ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Growth And Development ◽  
Biological Effects ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Myoblast Differentiation ◽  
Fatty Acid Binding ◽  
Knock Out ◽  
Early Differentiation

In mammals, Myostatin (MSTN) is a known negative regulator of muscle growth and development, but its role in birds is poorly understood. To investigate the molecular mechanism of MSTN on muscle growth and development in chickens, we knocked out MSTN in chicken fetal myoblasts (CFMs) and sequenced the mRNA transcriptomes. The amplicon sequencing results show that the editing efficiency of the cells was 76%. The transcriptomic results showed that 296 differentially expressed genes were generated after down-regulation of MSTN, including angiotensin I converting enzyme (ACE), extracellular fatty acid-binding protein (EXFABP) and troponin T1, slow skeletal type (TNNT1). These genes are closely associated with myoblast differentiation, muscle growth and energy metabolism. Subsequent enrichment analysis showed that DEGs of CFMs were related to MAPK, P13K/AKT, and STAT3 signaling pathways. The MAPK and P13K/AKT signaling pathways are two of the three known signaling pathways involved in the biological effects of MSTN in mammals, and the STAT3 pathway is also significantly enriched in MSTN knock out chicken leg muscles. The results of this study will help to understand the possible molecular mechanism of MSTN regulating the early differentiation of CFMs and lay a foundation for further research on the molecular mechanism of MSTN involvement in muscle growth and development.

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