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Ischemic Stroke Induces Skeletal Muscle Damage and Alters Transcriptome Profile in Rats.

ABSTRACT: To establish pathological features of skeletal muscle post-stroke and to provide a background for promising interventions. Adult male SD rats were selected and randomly divided into a control group, a sham group, and a middle cerebral artery occlusion (MCAO) group. The tolerance and capability of exercise were separately collected on days 1, 3, 5, and 7 after the MCAO operation. The neurological deficits, brain infarct volume, soleus histopathology, mRNA-seq analysis, flow cytometry, immunofluorescence, and protein expression analysis were performed on the seventh day. Rats in the MCAO group showed that soleus tissue weight, pulling force, exercise capacity, endurance, and muscle structure were significantly decreased. Moreover, the RNA sequencing array revealed that mitochondrial-mediated autophagy was the critical pathological process, and the result of transcriptomic findings was confirmed at the translational level. The mitochondrial membrane potential and the mfn2 and p62 protein expression were decreased, and the Beclin-1, ATG5, Parkin, PINK1, LC3B, and Drp1 expression were upregulated; these results were consistent with immunohistochemistry. This is the first report on the pathological features of limbic symptoms on day 7 after MCAO surgery in rats. In addition, we further confirmed that autophagy is one of the main causative mechanisms of reduced muscle function after stroke.

SUBMITTER: Qi H

PROVIDER: S-EPMC9865444 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Ischemic Stroke Induces Skeletal Muscle Damage and Alters Transcriptome Profile in Rats.

Qi Hu H Li Xiangyu X Zhang Xiumeng X Li Bin B Tian Dan D Wang Dejian D Yang Ruocong R Zeng Nan N

Journal of clinical medicine 20230109 2

To establish pathological features of skeletal muscle post-stroke and to provide a background for promising interventions. Adult male SD rats were selected and randomly divided into a control group, a sham group, and a middle cerebral artery occlusion (MCAO) group. The tolerance and capability of exercise were separately collected on days 1, 3, 5, and 7 after the MCAO operation. The neurological deficits, brain infarct volume, soleus histopathology, mRNA-seq analysis, flow cytometry, immunofluor ...[more]

PMID: 36675476

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

Project description:Background: Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets.Results: Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3?h post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n?=?12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p?<?0.05; n?=?23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common).Conclusions: The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<?1% of the differentially expressed genes) validated for this microarray did not reveal any sex differences. However, sex differences might be observed for other gene targets.

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Project description:BackgroundIn the past, numerous studies revealed that supplementation with carnitine has multiple effects on performance characteristics and gene expression in livestock and model animals. The molecular mechanisms underlying these observations are still largely unknown. Increasing evidence suggests that microRNAs (miRNAs), a class of small non-coding RNA molecules, play an important role in post-transcriptional regulation of gene expression and thereby influencing several physiological and pathological processes. Based on these findings, the aim of the present study was to investigate the influence of carnitine supplementation on the miRNA expression profile in skeletal muscle of obese Zucker rats using miRNA microarray analysis.ResultsObese Zucker rats supplemented with carnitine had higher concentrations of total carnitine in plasma and muscle than obese control rats (P < 0.05). miRNA expression profiling in skeletal muscle revealed a subset of 152 miRNAs out of the total number of miRNAs analysed (259) were identified to be differentially regulated (adjusted P-value < 0.05) by carnitine supplementation. Compared to the obese control group, 111 miRNAs were up-regulated and 41 down-regulated by carnitine supplementation (adjusted P-value < 0.05). 14 of these miRNAs showed a log2 ratio ≥ 0.5 and 7 miRNAs showed a log2 ratio ≤ -0.5 (adjusted P-value < 0.05). After confirmation by qRT-PCR, 11 miRNAs were found to be up-regulated and 6 miRNAs were down-regulated by carnitine supplementation (P < 0.05). Furthermore, a total of 1,446 target genes within the validated miRNAs were revealed using combined three bioinformatic algorithms. Analysis of Gene Ontology (GO) categories and KEGG pathways of the predicted targets revealed that carnitine supplementation regulates miRNAs that target a large set of genes involved in protein-localization and -transport, regulation of transcription and RNA metabolic processes, as well as genes involved in several signal transduction pathways, like ubiquitin-mediated proteolysis and longterm depression, are targeted by the miRNAs regulated by carnitine supplementation.ConclusionThe present study shows for the first time that supplementation of carnitine affects a large set of miRNAs in skeletal muscle of obese Zucker rats suggesting a novel mechanism through which carnitine exerts its multiple effects on gene expression, which were observed during the past.

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Ischemic Stroke Induces Skeletal Muscle Damage and Alters Transcriptome Profile in Rats.

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Ischemic Stroke Induces Skeletal Muscle Damage and Alters Transcriptome Profile in Rats.

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