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

Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice

2015 ◽  
Vol 308 (10) ◽  
pp. E912-E920 ◽  
Author(s):  
Timo Kanzleiter ◽  
Markus Jähnert ◽  
Gunnar Schulze ◽  
Joachim Selbig ◽  
Nicole Hallahan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Dna Methylation ◽  
Exercise Training ◽  
Metabolic Regulation ◽  
Muscle Growth ◽  
Epigenetic Mechanism ◽  
Myogenic Regulatory Factors ◽  
Regulatory Factors ◽  
A Genome

The adaptive response of skeletal muscle to exercise training is tightly controlled and therefore requires transcriptional regulation. DNA methylation is an epigenetic mechanism known to modulate gene expression, but its contribution to exercise-induced adaptations in skeletal muscle is not well studied. Here, we describe a genome-wide analysis of DNA methylation in muscle of trained mice ( n = 3). Compared with sedentary controls, 2,762 genes exhibited differentially methylated CpGs ( P < 0.05, meth diff >5%, coverage >10) in their putative promoter regions. Alignment with gene expression data ( n = 6) revealed 200 genes with a negative correlation between methylation and expression changes in response to exercise training. The majority of these genes were related to muscle growth and differentiation, and a minor fraction involved in metabolic regulation. Among the candidates were genes that regulate the expression of myogenic regulatory factors ( Plexin A2) as well as genes that participate in muscle hypertrophy ( Igfbp4) and motor neuron innervation ( Dok7). Interestingly, a transcription factor binding site enrichment study discovered significantly enriched occurrence of CpG methylation in the binding sites of the myogenic regulatory factors MyoD and myogenin. These findings suggest that DNA methylation is involved in the regulation of muscle adaptation to regular exercise training.

scholarly journals Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

2015 ◽  
Vol 309 (4) ◽  
pp. H685-H691 ◽  
Author(s):  
Raymond D. Devine ◽  
Sabahattin Bicer ◽  
Peter J. Reiser ◽  
Markus Velten ◽  
Loren E. Wold
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Muscle Dysfunction ◽  
Skeletal Muscle Dysfunction ◽  
Gene And Protein Expression ◽  
Muscle Remodeling

Cardiac and skeletal muscle dysfunction is a recognized effect of cancer-induced cachexia, with alterations in heart function leading to heart failure and negatively impacting patient morbidity. Cachexia is a complex and multifaceted disease state with several potential contributors to cardiac and skeletal muscle dysfunction. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading components of the extracellular matrix (ECM). Changes to the ECM cause disruption both in the connections between cells at the basement membrane and in cell-to-cell interactions. In the present study, we used a murine model of C26 adenocarcinoma-induced cancer cachexia to determine changes in MMP gene and protein expression in cardiac and skeletal muscle. We analyzed MMP-2, MMP-3, MMP-9, and MMP-14 as they have been shown to contribute to both cardiac and skeletal muscle ECM changes and, thereby, to pathology in models of heart failure and muscular dystrophy. In our model, cardiac and skeletal muscles showed a significant increase in RNA and protein levels of several MMPs and tissue inhibitors of metalloproteinases. Cardiac muscle showed significant protein increases in MMP-2, MMP-3, MMP-9, and MMP-14, whereas skeletal muscles showed increases in MMP-2, MMP-3, and MMP-14. Furthermore, collagen deposition was increased after C26 adenocarcinoma-induced cancer cachexia as indicated by an increased left ventricular picrosirius red-positive-stained area. Increases in serum hydroxyproline suggest increased collagen turnover, implicating skeletal muscle remodeling. Our findings demonstrate that cancer cachexia-associated matrix remodeling results in cardiac fibrosis and possible skeletal muscle remodeling. With these findings, MMPs represent a possible therapeutic target for the treatment of cancer-induced cachexia.

scholarly journals PDGFRα mediated survival of myofibroblasts inhibit satellite cell proliferation during aberrant regeneration of lacerated skeletal muscle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abinaya Sundari Thooyamani ◽  
Asok Mukhopadhyay
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Skeletal Muscle Regeneration ◽  
Tissue Architecture ◽  
Muscle Fibrosis ◽  
Molecular Events ◽  
Injury Model ◽  
Aberrant Regeneration ◽  
Muscle Remodeling

AbstractAberrant regeneration or fibrosis in muscle is the denouement of deregulated cellular and molecular events that alter original tissue architecture due to accumulation of excessive extracellular matrix. The severity of the insult to the skeletal muscle determines the nature of regeneration. Numerous attempts at deciphering the mechanism underlying fibrosis and the subsequent strategies of drug therapies have yielded temporary solutions. Our intent is to understand the interaction between the myofibroblasts (MFs) and the satellite cells (SCs), during skeletal muscle regeneration. We hypothesize that MFs contribute to the impairment of SCs function by exhibiting an antagonistic influence on their proliferation. A modified laceration based skeletal muscle injury model in mouse was utilized to evaluate the dynamics between the SCs and MFs during wound healing. We show that the decline in MFs’ number through inhibition of PDGFRα signaling consequently promotes proliferation of the SCs and exhibits improved skeletal muscle remodeling. We further conclude that in situ administration of PDGFRα inhibitor prior to onset of fibrosis may attenuate aberrant regeneration. This opens new possibility for the early treatment of muscle fibrosis by specific targeting of MFs rather than transplantation of SCs.

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.

scholarly journals Stem Cells for the Treatment of Skeletal Muscle Injury

2009 ◽  
Vol 28 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Andres J. Quintero ◽  
Vonda J. Wright ◽  
Freddie H. Fu ◽  
Johnny Huard
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Muscle Injury ◽  
Skeletal Muscle Injury

scholarly journals Modelling the skeletal muscle injury recovery using in vivo contrast-enhanced micro-CT: a proof-of-concept study in a rat model

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Bruno Paun ◽  
Daniel García Leon ◽  
Alex Claveria Cabello ◽  
Roso Mares Pages ◽  
Elena de la Calle Vargas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Rat Model ◽  
Muscle Injury ◽  
Micro Ct ◽  
Skeletal Muscle Injury ◽  
Monitoring Time ◽  
Contrast Enhanced Ct ◽  
Contrast Enhanced ◽  
Injury Recovery

Abstract Background Skeletal muscle injury characterisation during healing supports trauma prognosis. Given the potential interest of computed tomography (CT) in muscle diseases and lack of in vivo CT methodology to image skeletal muscle wound healing, we tracked skeletal muscle injury recovery using in vivo micro-CT in a rat model to obtain a predictive model. Methods Skeletal muscle injury was performed in 23 rats. Twenty animals were sorted into five groups to image lesion recovery at 2, 4, 7, 10, or 14 days after injury using contrast-enhanced micro-CT. Injury volumes were quantified using a semiautomatic image processing, and these values were used to build a prediction model. The remaining 3 rats were imaged at all monitoring time points as validation. Predictions were compared with Bland-Altman analysis. Results Optimal contrast agent dose was found to be 20 mL/kg injected at 400 μL/min. Injury volumes showed a decreasing tendency from day 0 (32.3 ± 12.0mm3, mean ± standard deviation) to day 2, 4, 7, 10, and 14 after injury (19.6 ± 12.6, 11.0 ± 6.7, 8.2 ± 7.7, 5.7 ± 3.9, and 4.5 ± 4.8 mm3, respectively). Groups with single monitoring time point did not yield significant differences with the validation group lesions. Further exponential model training with single follow-up data (R2 = 0.968) to predict injury recovery in the validation cohort gave a predictions root mean squared error of 6.8 ± 5.4 mm3. Further prediction analysis yielded a bias of 2.327. Conclusion Contrast-enhanced CT allowed in vivo tracking of skeletal muscle injury recovery in rat.

Sign in / Sign up

Export Citation Format

Share Document