Investigating Transcriptional Dynamics Changes and Time-Dependent Marker Gene Expression in the Early Period After Skeletal Muscle Injury in Rats.
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ABSTRACT:
SUBMITTER: Ren K
PROVIDER: S-EPMC8248501 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Pressure ulcers (PUs) are a major clinical problem that constitutes a tremendous economic burden on healthcare systems. Deep tissue injury (DTI) is a unique serious type of pressure ulcer that arises in skeletal muscle tissue. DTI arises in part because skeletal muscle tissues are more susceptible than skin to external compression. Unfortunately, few effective therapies are currently available for muscle injury. Basic fibroblast growth factor (bFGF), a potent mitogen and survival factor for various cells, plays a crucial role in the regulation of muscle development and homeostasis. The main purpose of this study was to test whether local administration of bFGF could accelerate muscle regeneration in a rat DTI model. METHODS:Male Sprague Dawley (SD) rats (age 12 weeks) were individually housed in plastic cages and a DTI PU model was induced according to methods described before. Animals were randomly divided into three groups: a normal group, a PU group treated with saline, and a PU group treated with bFGF (10 ?g/0.1 ml) subcutaneously near the wound. RESULTS:We found that application of bFGF accelerated the rate of wound closure and promoted cell proliferation and tissue angiogenesis. In addition, compared to saline administration, bFGF treatment prevented collagen deposition, a measure of fibrosis, and up-regulated the myogenic marker proteins MyHC and myogenin, suggesting bFGF promoted injured muscle regeneration. Moreover, bFGF treatment increased levels of myogenesis-related proteins p-Akt and p-mTOR. CONCLUSIONS:Our findings show that bFGF accelerated injured skeletal muscle regeneration through activation of the PI3K/Akt/mTOR signaling pathway and suggest that administration of bFGF is a potential therapeutic strategy for the treatment of skeletal muscle injury in PUs.
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Project description:Vagus nerve stimulation (VNS) has a protective effect on distal organ injury after ischemia/reperfusion (I/R) injury. We aimed to investigate the protective efficacy of VNS on hepatic I/R injury-induced acute skeletal muscle injury and explore its underlying mechanisms. To test this hypothesis, male Sprague-Dawley rats were randomly divided into three groups: sham group (sham operation, n = 6); I/R group (hepatic I/R with sham VNS, n = 6); and VNS group (hepatic I/R with VNS, n = 6). A hepatic I/R injury model was prepared by inducing hepatic ischemia for 1 h (70%) followed by hepatic reperfusion for 6 h. VNS was performed during the entire hepatic I/R process. Tissue and blood samples were collected at the end of the experiment for biochemical assays, molecular biological preparations, and histological examination. Our results showed that throughout the hepatic I/R process, VNS significantly reduced inflammation, oxidative stress, and apoptosis, while significantly increasing the protein levels of silent information regulator 1 (SIRT1) and decreasing the levels of acetylated forkhead box O1 and Ac-p53, in the skeletal muscle. These data suggest that VNS can alleviate hepatic I/R injury-induced acute skeletal muscle injury by suppressing inflammation, oxidative stress, and apoptosis, potentially via the SIRT1 pathway.
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Project description:The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and corrected with treadmill training. The BMP pathway was differentially activated with early treadmill training as shown by Ingenuity Pathway Analysis. The expression of several muscle mass regulators was modulated by treadmill training, including Fst, Jun, Bmpr2, Actr2b, and Smad3. In addition, key players in fatty acids metabolism (Lpl and Fabp3) responded to both SCI induced inactivity and reloading with training. The decrease in Smad3 and Fst early after the initiation of treadmill training was confirmed by RT-PCR. Our data suggest that TGFβ/Smad3 signaling may be mainly involved in the decrease in muscle mass observed with SCI, while the BMP pathway was activated with treadmill training.
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Project description:In terrestrial locomotion, muscles undergo damped oscillations in response to limb impacts with the ground. Muscles are also actuators that generate mechanical power to allow locomotion. The corresponding elementary contractile process is the work stroke of an actin-myosin cross-bridge, which may be forcibly detached by superposed oscillations. By experimentally emulating rat leg impacts, we found that full activity and non-fatigue must meet to possibly prevent forcible cross-bridge detachment. Because submaximal muscle force represents the ordinary locomotor condition, our results show that forcible, eccentric cross-bridge detachment is a common, physiological process even during isometric muscle contractions. We also calculated the stiffnesses of the whole muscle-tendon complex and the fibre material separately, as well as Young's modulus of the latter: 1.8 MPa and 0.75 MPa for fresh, fully active and passive fibres, respectively. Our inferred Young's modulus of the tendon-aponeurosis complex suggests that stiffness in series to the fibre material is determined by the elastic properties of the aponeurosis region, rather than the tendon material. Knowing these stiffnesses and the muscle mass, the complex' eigenfrequency for responses to impacts can be quantified, as well as the size-dependency of this time scale of muscular wobbling mass dynamics.
| S-EPMC5643554 | biostudies-literature
Project description:Skeletal muscle is a heterogeneous tissue comprised of muscle fiber and mononuclear cell types that, in addition to movement, influences immunity, metabolism and cognition. We investigated the gene expression patterns of skeletal muscle cells using RNA-seq of subtype-pooled single human muscle fibers and single cell RNA-seq of mononuclear cells from human vastus lateralis, mouse quadriceps, and mouse diaphragm. We identified 11 human skeletal muscle mononuclear cell types, including two fibro-adipogenic progenitor (FAP) cell subtypes. The human FBN1+ FAP cell subtype is novel and a corresponding FBN1+ FAP cell type was also found in single cell RNA-seq analysis in mouse. Transcriptome exercise studies using bulk tissue analysis do not resolve changes in individual cell-type proportion or gene expression. The cell-type gene signatures provide the means to use computational methods to identify cell-type level changes in bulk studies. As an example, we analyzed public transcriptome data from an exercise training study and revealed significant changes in specific mononuclear cell-type proportions related to age, sex, acute exercise and training. Our single-cell expression map of skeletal muscle cell types will further the understanding of the diverse effects of exercise and the pathophysiology of muscle disease.
| S-EPMC6959232 | biostudies-literature
Project description: Not available
| S-EPMC11242864 | biostudies-literature
Project description:Severe burn trauma is generally followed by a catabolic response that leads to muscle wasting and weakness affecting skeletal musculature. Here, we perform whole-genome expression and in vivo NMR spectroscopy studies to define respectively the full set of burn-induced changes in skeletal muscle gene expression and the role of mitochondria in the altered energy expenditure exhibited by burn patients. Our results show 1,136 genes differentially expressed in a mouse hind limb burn model and identify expression pattern changes of genes involved in muscle development, protein degradation and biosynthesis, inflammation, and mitochondrial energy and metabolism. To assess further the role of mitochondria in burn injury, we performed in vivo (31)P NMR spectroscopy on hind limb skeletal muscle, to noninvasively measure high-energy phosphates and the effect of magnetization transfer on inorganic phosphate (P(i)) and phosphocreatine (PCr) resonances during saturation of gammaATP resonance, mediated by the ATP synthesis reactions. Although local burn injury does not alter high-energy phosphates or pH, apart from PCr reduction, it does significantly reduce the rate of ATP synthesis, to further implicate a role for mitochondria in burn trauma. These results, in conjunction with our genomic results showing down-regulation of mitochondrial oxidative phosphorylation and related functions, strongly suggest alterations in mitochondrial-directed energy expenditure reactions, advancing our understanding of skeletal muscle dysfunction suffered by burn injury patients.
| S-EPMC556259 | biostudies-literature
Project description:PurposeEvaluate the relationship between muscle microstructure, diffusion time (Δ), and the diffusion tensor (DT) to identify the optimal Δ where changes in muscle fiber size may be detected.MethodsThe DT was simulated in models with histology informed geometry over a range of Δ with a stimulated echo DT imaging (DTI) sequence using the numerical simulation application DifSim. The difference in the DT at each Δ between healthy and injured skeletal muscle models was calculated, to identify the optimal Δ at which changes in muscle fiber size may be detected. The random permeable barrier model (RPBM) was used to estimate muscle microstructure from the simulated DT measurements, which were compared to the ground truth.ResultsAcross all models, fractional anisotropy provided greater contrast between injured and control models than diffusivity measurements. Compared to control models, in atrophic injury models, the greatest difference in the DT was found between 90 ms and 250 ms. In models with acute edema, the contrast between injured and control muscle increased with increasing diffusion time, although these models had smaller mean fiber areas. RPBM systematically underestimated fiber size but accurately estimated surface area-to-volume ratio of simulated models.ConclusionThese findings may better inform pulse sequence parameter selection when performing DTI experiments in vivo. If only a single diffusion experiment can be performed, the selected Δ should be ~170 ms to maximize the ability to discriminate between different injury models. Ideally several diffusion times between 90 ms and 500 ms should be sampled in order to maximize diffusion contrast, particularly when the disease process is unknown.
| S-EPMC8204931 | biostudies-literature
Project description:BackgroundCancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences.ResultsWe found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC.ConclusionOur findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice.
| S-EPMC10318789 | biostudies-literature
Project description:BACKGROUND: Myoblasts undergo major changes in their plasma membrane during the initial steps of skeletal muscle differentiation, including major alterations in the distribution of cholesterol. Cholesterol is involved in crucial membrane functions, such as fluidity, and permeability, and in the organization of specialized membrane microdomains (or lipid rafts). We have previously shown that alterations in cholesterol levels in myoblasts induce changes in proliferation and differentiation, which involves activation of Wnt/beta-catenin signaling pathway. In this study we used methyl-?-cyclodextrin (MbCD) to extract cholesterol from the membrane of chick skeletal muscle cells grown in culture. Using Ion Torrent-based sequencing, we compared the transcriptome of untreated and MbCD treated cells. Our aim was to define the genes that are expressed in these two conditions and relate their expression to cellular functions. RESULTS: Over 5.7 million sequences were obtained, representing 671.38 Mb of information. mRNA transcriptome profiling of myogenic cells after cholesterol depletion revealed alterations in transcripts involved in the regulation of apoptosis, focal adhesion, phagosome, tight junction, cell cycle, lysosome, adherens junctions, gap junctions, p53 signaling pathway, endocytosis, autophagy and actin cytoskeleton. Lim domain only protein 7 mRNA was found to be the highest up-regulated feature after cholesterol depletion. CONCLUSIONS: This is the first study on the effects of membrane cholesterol depletion in mRNA expression in myogenic cells. Our data shows that alterations in the availability of plasma membrane cholesterol lead to transcriptional changes in myogenic cells. The knowledge of the genes involved in the cellular response to cholesterol depletion could contribute to our understanding of skeletal muscle differentiation.
| S-EPMC4092213 | biostudies-literature