scholarly journals Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs

2005 ◽  
Vol 288 (1) ◽  
pp. E92-E105 ◽  
Author(s):  
Anthony D. Gagliardi ◽  
Evan Y. W. Kuo ◽  
Sanda Raulic ◽  
Graham F. Wagner ◽  
Gabriel E. DiMattia
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Growth Retardation ◽  
Bone Development ◽  
Muscle Growth ◽  
Growth Inhibitor ◽  
Neonatal Morbidity ◽  
Postnatal Growth ◽  
Adult Mice ◽  
Potent Growth

Stanniocalcin (STC)-2 was discovered by its primary amino acid sequence identity to the hormone STC-1. The function of STC-2 has not been examined; thus we generated two lines of transgenic mice overexpressing human (h)STC-2 to gain insight into its potential functions through identification of overt phenotypes. Analysis of mouse Stc2 gene expression indicates that, unlike Stc1, it is not highly expressed during development but exhibits overlapping expression with Stc1 in adult mice, with heart and skeletal muscle exhibiting highest steady-state levels of Stc2 mRNA. Constitutive overexpression of hSTC-2 resulted in pre- and postnatal growth restriction as early as embryonic day 12.5, progressing such that mature hSTC-2-transgenic mice are ∼45% smaller than wild-type littermates. hSTC-2 overexpression is sometimes lethal; we observed 26–34% neonatal morbidity without obvious dysmorphology. hSTC-2-induced growth retardation is associated with developmental delay, most notably cranial suture formation. Organ allometry studies show that hSTC-2-induced dwarfism is associated with testicular organomegaly and a significant reduction in skeletal muscle mass likely contributing to the dwarf phenotype. hSTC-2-transgenic mice are also hyperphagic, but this does not result in obesity. Serum Ca2+ and PO4 were unchanged in hSTC-2-transgenic mice, although STC-1 can regulate intra- and extracellular Ca2+ in mammals. Interestingly, severe growth retardation induced by hSTC-2 is not associated with a decrease in GH or IGF expression. Consequently, similar to STC-1, STC-2 can act as a potent growth inhibitor and reduce intramembranous and endochondral bone development and skeletal muscle growth, implying that these tissues are specific physiological targets of stanniocalcins.

The chicken skeletal muscle alpha-actin promoter is tissue specific in transgenic mice

1989 ◽  
Vol 9 (9) ◽  
pp. 3785-3792
Author(s):  
C J Petropoulos ◽  
M P Rosenberg ◽  
N A Jenkins ◽  
N G Copeland ◽  
S H Hughes
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Striated Muscle ◽  
Transcriptional Start Site ◽  
Actin Gene ◽  
Tissue Specific ◽  
Adult Mice ◽  
Transgenic Lines ◽  
Alpha Actin ◽  
Chicken Skeletal Muscle

We have generated transgenic mouse lines that carry the promoter region of the chicken skeletal muscle alpha (alpha sk) actin gene linked to the bacterial chloramphenicol acetyltransferase (CAT) gene. In adult mice, the pattern of transgene expression resembled that of the endogenous alpha sk actin gene. In most of the transgenic lines, high levels of CAT activity were detected in striated muscle (skeletal and cardiac) but not in the other tissues tested. In striated muscle, transcription of the transgene was initiated at the normal transcriptional start site of the chicken alpha sk actin gene. The region from nucleotides -191 to +27 of the chicken alpha sk actin gene was sufficient to direct the expression of CAT in striated muscle of transgenic mice. These observations suggest that the mechanism of tissue-specific actin gene expression is well conserved in higher vertebrate species.

scholarly journals Heterogeneous origins and functions of mouse skeletal muscle-resident macrophages

2020 ◽  
Vol 117 (34) ◽  
pp. 20729-20740 ◽  
Author(s):  
Xingyu Wang ◽  
Adwait Amod Sathe ◽  
Gregory R. Smith ◽  
Frederique Ruf-Zamojski ◽  
Venugopalan Nair ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Fetal Liver ◽  
Muscle Growth ◽  
Marrow Transplant ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Adult Mice ◽  
Wide Range ◽  
Functionally Diverse

Tissue-resident macrophages can originate from embryonic or adult hematopoiesis. They play important roles in a wide range of biological processes including tissue remodeling during organogenesis, organ homeostasis, repair following injury, and immune response to pathogens. Although the origins and tissue-specific functions of resident macrophages have been extensively studied in many other tissues, they are not well characterized in skeletal muscle. In the present study, we have characterized the ontogeny of skeletal muscle-resident macrophages by lineage tracing and bone marrow transplant experiments. We demonstrate that skeletal muscle-resident macrophages originate from both embryonic hematopoietic progenitors located within the yolk sac and fetal liver as well as definitive hematopoietic stem cells located within the bone marrow of adult mice. Single-cell-based transcriptome analyses revealed that skeletal muscle-resident macrophages are distinctive from resident macrophages in other tissues as they express a distinct complement of transcription factors and are composed of functionally diverse subsets correlating to their origins. Functionally, skeletal muscle-resident macrophages appear to maintain tissue homeostasis and promote muscle growth and regeneration.

High methionine diet in skeletal muscle remodeling: Epigenetic mechanism of homocysteine mediated growth retardation

2020 ◽  
Author(s):  
Mahavir Singh ◽  
Akash K George ◽  
Wintana Eyob ◽  
Rubens Petit Homme ◽  
Dragana Stanisic ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Retardation ◽  
Muscle Injury ◽  
Muscle Growth ◽  
Epigenetic Mechanism ◽  
Muscle Dysfunction ◽  
Cystathionine Beta Synthase ◽  
Musculoskeletal Abnormalities ◽  
Metalloproteinase Activity ◽  
Muscle Remodeling

Epigenetic DNA methylation is crucial for gene-imprinting/off-printing ensuring epigenetic memory but generates copious homocysteine (Hcy) unequivocally. That is why during pregnancy mothers are recommended ‘folic acid’ to avoid birth-defects because of elevated Hcy levels (hyperhomocysteinemia; HHcy). Children born with HHcy have musculoskeletal abnormalities/growth retardation. We focus on gut-dysbiotic microbiome implication that instigates “1-carbon metabolism” and HHcy causing growth retardation along with muscle abnormalities. We test hypothesis whether high methionine diet (HMD, an amino acid high in red-meat) a substrate for Hcy can cause skeletal muscle and growth retardation and treatment with probiotics (PB) mitigate muscle dysfunction. We employed cystathionine beta synthase; CBS deficient mouse; CBS+/- fed with/without HMD and with/without a probiotic in drinking water for 16 weeks. Matrix metalloproteinase activity; a hallmark of remodeling was measured by zymography. Muscle functions were scored via electric stimulation. Our results suggest that compared to WT, CBS+/- mice exhibited reduced growth. MMP-2 activity was robust in CBS+/- and HMD effects were attenuated by PB intervention. Electrical stimulation magnitude was decreased in CBS+/- and CBS+/- treated with HMD. Interestingly; PB mitigated muscle growth retardation and atrophy. Collectively, results imply that individuals with mild/moderate HHcy seem more prone to skeletal muscle injury and its dysfunction

scholarly journals The chicken skeletal muscle alpha-actin promoter is tissue specific in transgenic mice.

1989 ◽  
Vol 9 (9) ◽  
pp. 3785-3792 ◽  
Author(s):  
C J Petropoulos ◽  
M P Rosenberg ◽  
N A Jenkins ◽  
N G Copeland ◽  
S H Hughes
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Striated Muscle ◽  
Transcriptional Start Site ◽  
Actin Gene ◽  
Tissue Specific ◽  
Adult Mice ◽  
Transgenic Lines ◽  
Alpha Actin ◽  
Chicken Skeletal Muscle

We have generated transgenic mouse lines that carry the promoter region of the chicken skeletal muscle alpha (alpha sk) actin gene linked to the bacterial chloramphenicol acetyltransferase (CAT) gene. In adult mice, the pattern of transgene expression resembled that of the endogenous alpha sk actin gene. In most of the transgenic lines, high levels of CAT activity were detected in striated muscle (skeletal and cardiac) but not in the other tissues tested. In striated muscle, transcription of the transgene was initiated at the normal transcriptional start site of the chicken alpha sk actin gene. The region from nucleotides -191 to +27 of the chicken alpha sk actin gene was sufficient to direct the expression of CAT in striated muscle of transgenic mice. These observations suggest that the mechanism of tissue-specific actin gene expression is well conserved in higher vertebrate species.

scholarly journals The influence of undernutrition during gestation on skeletal muscle cellularity and on the expression of genes that control muscle growth

2004 ◽  
Vol 91 (3) ◽  
pp. 331-339 ◽  
Author(s):  
Stéphanie Bayol ◽  
Doiran Jones ◽  
Geoffrey Goldspink ◽  
Neil C. Stickland
Keyword(s):  
Skeletal Muscle ◽  
Growth Rate ◽  
Muscle Growth ◽  
Postnatal Growth ◽  
Nuclear Antigen ◽  
Control Group ◽  
Muscle Fibres ◽  
Control Muscle ◽  
Expression Of Genes ◽  
Ad Libitum

We examined the effects of two levels of gestational undernutrition (50% and 40% of ad libitum) on postnatal growth rate, skeletal muscle cellularity and the expression of genes that control muscle growth, in the offspring at weaning. The results showed that the rat pups born to mothers fed the 50% diet during gestation and a control diet during lactation had an increased postnatal growth rate compared with the pups fed the more restricted diet (40% of ad libitum). Surprisingly, the growth rate of the control group (ad libitum) was intermediate between the 50% and 40% groups. The restricted diets did not alter the number of muscle fibres in the semitendinosus muscle of the offspring but the number of muscle nuclei was reduced by 16% in the 40% group compared with the control group. In the 50% group, the lightest pups at birth (L) had elevated muscle insulin-like growth factor (IGF)-1, IGF binding protein (BP)-5 and proliferating cell nuclear antigen (PCNA) mRNA compared with the L pups from both the control and 40% groups. The heaviest pups at birth (H) in the 50% group had increased levels of IGFBP-4, PCNA and M-cadherin mRNA compared with both the control and 40% groups. Levels of IGF-1 receptor, myostatin and MyoD mRNA did not correlate with postnatal growth. Both H and L pups from the 40% group had reduced muscle IGF-1 mRNA but all other transcripts examined were similar to control levels. The results suggest that the increased postnatal growth rate, which accompanied milder fetal undernutrition (50%), may be due to a more active local muscle IGF system and increased muscle-cell proliferation.

scholarly journals Changes in Myonuclear Number During Postnatal Growth –Implications for AAV Gene Therapy for Muscular Dystrophy

2021 ◽  
pp. 1-8
Author(s):  
Jennifer Morgan ◽  
Francesco Muntoni
Keyword(s):  
Skeletal Muscle ◽  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Growth ◽  
Postnatal Growth ◽  
Muscle Fibres ◽  
Postnatal Life ◽  
Adult Skeletal Muscle ◽  
Dividing Cells

Adult skeletal muscle is a relatively stable tissue, as the multinucleated muscle fibres contain post-mitotic myonuclei. During early postnatal life, muscle growth occurs by the addition of skeletal muscle stem cells (satellite cells) or their progeny to growing muscle fibres. In Duchenne muscular dystrophy, which we shall use as an example of muscular dystrophies, the muscle fibres lack dystrophin and undergo necrosis. Satellite-cell mediated regeneration occurs, to repair and replace the necrotic muscle fibres, but as the regenerated muscle fibres still lack dystrophin, they undergo further cycles of degeneration and regeneration. AAV gene therapy is a promising approach for treating Duchenne muscular dystrophy. But for a single dose of, for example, AAV coding for dystrophin, to be effective, the treated myonuclei must persist, produce sufficient dystrophin and a sufficient number of nuclei must be targeted. This latter point is crucial as AAV vector remains episomal and does not replicate in dividing cells. Here, we describe and compare the growth of skeletal muscle in rodents and in humans and discuss the evidence that myofibre necrosis and regeneration leads to the loss of viral genomes within skeletal muscle. In addition, muscle growth is expected to lead to the dilution of the transduced nuclei especially in case of very early intervention, but it is not clear if growth could result in insufficient dystrophin to prevent muscle fibre breakdown. This should be the focus of future studies.

scholarly journals Molecular regulation of skeletal muscle tissue formation and development

2018 ◽  
Vol 63 (No. 11) ◽  
pp. 489-499
Author(s):  
M. Nesvadbova ◽  
G. Borilova
Keyword(s):  
Skeletal Muscle ◽  
Molecular Genetic ◽  
Muscle Growth ◽  
Postnatal Growth ◽  
The Body ◽  
Meat Production ◽  
Muscle Fibres ◽  
Tissue Formation ◽  
Fibre Growth ◽  
Myogenic Factors

This article provides a complex overview of the different stages of myogenesis with an emphasis on the molecular, genetic and cellular bases for skeletal muscle growth. Animals with higher number of medium-sized muscle fibres produce meat of higher quality and in higher quantity. The number of muscle fibres that are created in the body is largely decided during the process of myogenesis. This review describes the main stages of embryonic skeletal myogenesis and the myogenic factors that control myogenesis in epaxial and hypaxial somites, limbs, the head and neck as well as postnatal muscle fibre growth and regeneration. An understanding of the molecular and genetic factors influencing the prenatal and postnatal growth of skeletal muscle is essential for the development of the new strategies and practical approaches to meat production.

Increased fat mass, decreased myofiber size, and a shift to glycolytic muscle metabolism in adolescent male transgenic mice overexpressing IGFBP-2

2010 ◽  
Vol 299 (2) ◽  
pp. E287-E298 ◽  
Author(s):  
Charlotte Rehfeldt ◽  
Ulla Renne ◽  
Mandy Sawitzky ◽  
Gerhard Binder ◽  
Andreas Hoeflich
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Muscle Growth ◽  
Muscle Metabolism ◽  
Adolescent Male ◽  
Signal Molecules ◽  
Fat Percentage ◽  
Ki 67 ◽  
Phosphorylated Akt

To elucidate the functional role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) for in vivo skeletal muscle growth and function, skeletal muscle cellularity and metabolism, expression of signal molecules, and body growth and composition were studied in a transgenic mouse model overexpressing IGFBP-2. Postnatal growth rate of transgenic mice was reduced from day 21 of age by 6–8% compared with nontransgenic controls. At 10 wk of age body lean protein and moisture percentages were lower, whereas fat percentage was higher in IGFBP-2 transgenic mice. Muscle weights were reduced (−13% on day 30 of age, −14% on day 72), which resulted from slower growth of myofibers in size but not from decreases in myofiber number. The reduction in muscle mass was associated with lower total DNA, RNA, and protein contents as well as greater DNA/RNA and protein/RNA ratios. The percentage of proliferating (Ki-67-positive) nuclei within myofibers was reduced (3.4 vs. 5.8%) in 30-day-old transgenic mice. These changes were accompanied by slight reductions in specific p44/42 MAPK activity (−18% on day 72) and, surprisingly, by increased levels of phosphorylated Akt (Ser473) (+25% on day 30, +66% on day 72). The proportion of white glycolytic fibers (55.9 vs. 53.5%) and the activity of lactate dehydrogenase (+8%) were elevated in 72-day-old transgenic mice. Most of the differences observed between transgenic and nontransgenic mice were more pronounced in males. The results suggest that IGFBP-2 significantly inhibits postnatal skeletal myofiber growth by decreasing myogenic proliferation and protein accretion and enhances glycolytic muscle metabolism.

Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle

2007 ◽  
Vol 293 (6) ◽  
pp. E1772-E1781 ◽  
Author(s):  
Malin C. Levin ◽  
Mara Monetti ◽  
Matthew J. Watt ◽  
Mini P. Sajan ◽  
Robert D. Stevens ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Lipid Accumulation ◽  
Fatty Acyl ◽  
Whole Body ◽  
Lipid Deposition ◽  
Adult Mice ◽  
Insulin Tolerance

Insulin resistance and type 2 diabetes are frequently accompanied by lipid accumulation in skeletal muscle. However, it is unknown whether primary lipid deposition in skeletal muscle is sufficient to cause insulin resistance or whether the type of muscle fiber, oxidative or glycolytic fiber, is an important determinant of lipid-mediated insulin resistance. Here we utilized transgenic mice to test the hypothesis that lipid accumulation specifically in glycolytic muscle promotes insulin resistance. Overexpression of DGAT2, which encodes an acyl-CoA:diacylglycerol acyltransferase that catalyzes triacylglycerol (TG) synthesis, in glycolytic muscle of mice increased the content of TG, ceramides, and unsaturated long-chain fatty acyl-CoAs in young adult mice. This lipid accumulation was accompanied by impaired insulin signaling and insulin-mediated glucose uptake in glycolytic muscle and impaired whole body glucose and insulin tolerance. We conclude that DGAT2-mediated lipid deposition specifically in glycolytic muscle promotes insulin resistance in this tissue and may contribute to the development of diabetes.

scholarly journals Glycine receptor subunit-ß -deficiency in a mouse model of spasticity results in attenuated physical performance, growth and muscle strength

2020 ◽  
Author(s):  
Cintia Rivares ◽  
Alban Vignaud ◽  
Wendy Noort ◽  
Bastijn Koopmans ◽  
Maarten Loos ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Physical Performance ◽  
Motor Function ◽  
Glycine Receptor ◽  
Muscle Fibers ◽  
Muscle Growth ◽  
Skeletal Muscle Function ◽  
Cross Sectional ◽  
Adult Mice

AbstractSpasticity is the most common neurological disorder associated with increased muscle contraction causing impaired movement and gait. The aim of this study was to characterize physical performance and skeletal muscle function and phenotype of mice with a hereditary spastic mutation (B6.Cg-Glrbspa/J). Motor function, gait and physical activity of juvenile and adult spastic mice and the morphological, histological and mechanical characteristics of their soleus (SO) and gastrocnemius medialis (GM) muscles were compared with their wild-type (WT) littermates. Spastic mice showed attenuated growth, impaired motor function and low physical activity. Gait of spastic mice was characterized by a typical hopping pattern. Spastic mice showed lower muscle forces, which were related to the smaller physiological cross-sectional area of spastic muscles. The muscle-tendon complex length-force relationship of adult GM was shifted towards shorter lengths, which was explained by attenuated longitudinal tibia growth. Spastic GM was more fatigue resistant than WT GM. This was largely explained by a higher mitochondrial content in muscle fibers and relatively higher percentage of slow type muscle fibers. Muscles of juvenile spastic mice showed similar differences compared to WT juvenile mice, but these were less pronounced than between adult mice. This study shows that in spastic mice, disturbed motor function and gait is likely the result hyperactivity of skeletal muscle and impaired skeletal muscle growth, which progress with age.

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