Abstract P806: Sirtuin1 Plays a Critical Role in Reversing Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Junaith S Mohamed ◽  
Peter J Ferrandi ◽  
Paez G Hector ◽  
Christopher R Pitzer ◽  
Stephen E Alway
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Rna Seq ◽  
Stroke Patients ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that severely induces muscle wasting and weakness, which contributes more to the long-term functional disability in stroke patients than any other disease. Currently, no approved pharmacological drug is available to treat stroke-induced muscle loss. Rehabilitative therapy is the only available option to improve muscle function in stroke patients. However, higher muscle fatigability and lower muscle strength from extensive muscle wasting in post-stroke patients provide poor rehabilitative outcomes. As a result, about two-thirds of stroke survivors persist in a state of insufficient recovery and experience physical disability that drastically reduces their health and quality of life. The major challenge in the drug discovery effort for treating post-stroke muscle wasting is the lack of our understanding of the molecular and/or cellular mechanisms that underlie the muscle wasting in stroke. To understand the molecular origin of stroke-induced muscle atrophy, gene expression profiling and associated biological pathway enrichment studies were performed in a mouse model of cerebral ischemic stroke using high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq data revealed that the elevated atrophy in skeletal muscle observed in response to stroke was primairly associated with the altered expression of genes involved in the muscle protein degradation pathway. Further analysis of RNA-seq data identified Sirtuin1 (SirT1) as a critical protein that plays a significant role in regulating post-stroke muscle mass. SirT1 gain-of-function in skeletal muscle significantly reversed stroke-induced muscle atrophy via inhibiting the activation of the ubiquitin proteasomal pathway and restoring autophagy function. Collectively, this study identified suppression of SirT1as a novel mechanism by which stroke induces muscle atrophy.

scholarly journals Transcriptome Analysis of Skeletal Muscle Reveals Altered Proteolytic and Neuromuscular Junction Associated Gene Expressions in a Mouse Model of Cerebral Ischemic Stroke

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 726
Author(s):  
Peter J. Ferrandi ◽  
Mohammad Moshahid Khan ◽  
Hector G. Paez ◽  
Christopher R. Pitzer ◽  
Stephen E. Alway ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Neuromuscular Junction ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Altered Expression ◽  
Post Stroke ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Stroke is a leading cause of mortality and long-term disability in patients worldwide. Skeletal muscle is the primary systemic target organ of stroke that induces muscle wasting and weakness, which predominantly contribute to functional disability in stroke patients. Currently, no pharmacological drug is available to treat post-stroke muscle morbidities as the mechanisms underlying post-stroke muscle wasting remain poorly understood. To understand the stroke-mediated molecular changes occurring at the transcriptional level in skeletal muscle, the gene expression profiles and enrichment pathways were explored in a mouse model of cerebral ischemic stroke via high-throughput RNA sequencing and extensive bioinformatic analyses. RNA-seq revealed that the elevated muscle atrophy observed in response to stroke was associated with the altered expression of genes involved in proteolysis, cell cycle, extracellular matrix remodeling, and the neuromuscular junction (NMJ). These data suggest that stroke primarily targets muscle protein degradation and NMJ pathway proteins to induce muscle atrophy. Collectively, we for the first time have found a novel genome-wide transcriptome signature of post-stroke skeletal muscle in mice. Our study will provide critical information to further elucidate specific gene(s) and pathway(s) that can be targeted to mitigate accountable for post-stroke muscle atrophy and related weakness.

scholarly journals Muscle‐specific sirtuin1 gain‐of‐function ameliorates skeletal muscle atrophy in a pre‐clinical mouse model of cerebral ischemic stroke

2020 ◽  
Vol 2 (7) ◽  
pp. 387-397
Author(s):  
Kiril Tuntevski ◽  
Ameena Hajira ◽  
Austin Nichols ◽  
Stephen E. Alway ◽  
Junaith S. Mohamed
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Mouse Model ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Gain Of Function ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

scholarly journals Molecular Mechanisms of Skeletal Muscle Atrophy in Cerebral Ischemic Stroke

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Junaith Mohamed ◽  
Mohammad Khan ◽  
Peter Ferrandi ◽  
Hector Paez ◽  
Christopher Pitzer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ischemic Stroke ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

scholarly journals Cerebral Ischemic Stroke: is Gender Important?

2013 ◽  
Vol 33 (9) ◽  
pp. 1355-1361 ◽  
Author(s):  
Claire L Gibson
Keyword(s):  
Ischemic Stroke ◽  
Developed Countries ◽  
Cerebral Stroke ◽  
Clinical Investigations ◽  
Neuroprotective Strategies ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic ◽  
Gender Influences ◽  
Gender Specific

Cerebral stroke continues to be a major cause of death and the leading cause of long-term disability in developed countries. Evidence reviewed here suggests that gender influences various aspects of the clinical spectrum of ischemic stroke, in terms of influencing how a patients present with ischemic stroke through to how they respond to treatment. In addition, this review focuses on discussing the various pathologic mechanisms of ischemic stroke that may differ according to gender and compares how intrinsic and hormonal mechanisms may account for such gender differences. All clinical trials to date investigating putative neuroprotective treatments for ischemic stroke have failed, and it may be that our understanding of the injury cascade initiated after ischemic injury is incomplete. Revealing aspects of the pathophysiological consequences of ischemic stroke that are gender specific may enable gender relevant and effective neuroprotective strategies to be identified. Thus, it is possible to conclude that gender does, in fact, have an important role in ischemic stroke and must be factored into experimental and clinical investigations of ischemic stroke.

scholarly journals Post-stroke Hyperglycemia in Non-diabetic Ischemic Stroke is Related With Worse Functional Outcome: A Cohort Study

2021 ◽  
Vol 45 (5) ◽  
pp. 359-367
Author(s):  
Jin A Yoon ◽  
Yong-Il Shin ◽  
Deog Young Kim ◽  
Min Kyun Sohn ◽  
Jongmin Lee ◽  
...  
Keyword(s):  
Cohort Study ◽  
Ischemic Stroke ◽  
Glucose Level ◽  
Functional Outcomes ◽  
Stroke Patients ◽  
Nihss Score ◽  
Post Stroke ◽  
Significant Difference ◽  
Functional Assessments

Objective To investigate long-term and serial functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.Methods The Korean Stroke Cohort for Functioning and Rehabilitation (KOSCO) is a large, multi-center, prospective cohort study of stroke patients admitted to participating hospitals in nine areas of Korea. From KOSCO, ischemic stroke patients without diabetes were recruited and divided into two groups: patients without diabetes without (n=779) and with post-stroke hyperglycemia (n=223). Post-stroke hyperglycemia was defined as a glucose level >8 mmol/L. Functional assessments were performed 7 days and 3, 6, and 12 months after stroke onset.Results There were no significant differences in baseline characteristics between the groups, except in the age of onset and smoking. Analysis of the linear correlation between the initial National Institutes of Health Stroke Scale (NIHSS) score and glucose level showed no significant difference. Among our functional assessments, NIHSS, Fugl-Meyer Assessment (affected side), Functional Ambulatory Category, modified Rankin Scale, and Korean Mini-Mental State Examination (K-MMSE) showed statistically significant improvements in each group. All functional improvements except K-MMSE were significantly higher in patients without post-stroke hyperglycemia at 7 days and 3, 6, and 12 months.Conclusion The glucose level of ischemic stroke patients without diabetes had no significant correlation with the initial NIHSS score. The long-term effects of stress hyperglycemia showed worse functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.

scholarly journals The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Mrinal K. Ghosh ◽  
Dipankar Chakraborty ◽  
Sibani Sarkar ◽  
Arijit Bhowmik ◽  
Malini Basu
Keyword(s):  
Ischemic Stroke ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Early Stage ◽  
Significant Risk ◽  
Patient Death ◽  
Stroke Patients ◽  
Increased Risk ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Abstract Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences, ~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.

Abstract 158: Pre-existing Cancer Exacerbates Cerebral Ischemic Stroke in Mice via Regulatory T Cell Redistribution

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Long Wang ◽  
Yuxi Zhou ◽  
Weifeng Yu ◽  
Peiying Li
Keyword(s):  
Colon Cancer ◽  
Ischemic Stroke ◽  
Immune Cell ◽  
Infarct Volume ◽  
Ischemic Brain Injury ◽  
Stroke Patients ◽  
Ischemic Brain ◽  
Cerebral Ischemic Stroke ◽  
Neuro Inflammation ◽  
Cerebral Ischemic

Background and purpose: Accumulating epidemic evidence suggest that a considerable number of ischemic stroke patients had 1 or more cancer diagnosis before stroke attack. How the pre-existing cancer impact the cerebral ischemic injury is remarkably unknown. We tested the hypothesis that pre-existing cancer exacerbates cerebral ischemic stroke via regulatory T cell (Treg) redistribution. Methods: MC38 colon cancer cells or B16 melanoma cells were injected subcutaneously at the dose of 5*10 5 cells in 200μl PBS 3 weeks before distal middle cerebral artery occlusion (d-MCAO) surgery. Infarct volume was assessed at 3 days after surgery by staining the mice brain with 2,3,5-triphenyltetrazolium chloride. Sensorimotor assessments, such as body proprioception, climbing, forelimb walking, lateral turning, foot fault and adhesive removal were examined at 3, 5, 7, 14, 21 and 28 days after stroke. Neuro-inflammation was examined by measuring inflammatory cytokines with RT-PCR and immune cell infiltration using immunofluorescence and flow cytometry. Results: Pre-existing colon cancer and melanoma both exacerbated infarct volume growth in d-MCAO mice at 3 days after surgery. Mice with colon cancer exhibited prominently deterioration in their performance in sensorimotor functions after stroke compared with mice without cancer. Pre-existing colon cancer augmented peripheral immune cell infiltration into the ischemic brain but hindered Tregs’ recruitment into the brain. Cerebral ischemic stroke induced reduction in the number of Tregs in the peripheral blood were significantly aggravated in mice with pre-existing colon cancer. Depletion of Tregs with CD25 monoclonal antibody increased infarct volume in stroke mice but did not further exacerbate infarct growth in colon cancer stroke mice. Conclusion: Pre-existing cancer exacerbates ischemic brain injury and neuro-inflammation after stroke. Tregs redistribution plays an indispensable role in the cancer related deterioration of ischemic brain injury and may represent a promising target for treating stroke patients with pre-existing cancer.

scholarly journals Efficacy of sovateltide (IRL-1620) in a multicenter randomized controlled clinical trial in patients with acute cerebral ischemic stroke

2020 ◽  
Author(s):  
Anil Gulati ◽  
Nilesh Agrawal ◽  
Deepti Vibha ◽  
U.K. Misra ◽  
Birinder Paul ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Ischemic Stroke ◽  
Odds Ratio ◽  
Controlled Study ◽  
Stroke Patients ◽  
Neurological Outcomes ◽  
Number Of Patients ◽  
Cerebral Ischemic Stroke ◽  
Cerebral Ischemic

Background: Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective: To determine safety, tolerability and efficacy of sovateltide as an adjuvant to standard of care (SOC) in acute cerebral ischemic stroke patients. Methods: A prospective, multi-centric, randomized, double-blind, controlled study to compare efficacy of sovateltide in patients with acute cerebral ischemic stroke was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients who had stroke within the last 24 hours with a radiologic confirmation of ischemic stroke were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. All patients in both groups received SOC for stroke. Patients randomized in the sovateltide group received three doses of sovateltide (each dose 0.3 μg/kg) administered as an IV bolus over 1 minute at an interval of 3 hours ± 1 hour on day 1, day 3 and day 6 (total dose of 0.9 μg/kg/day). Patients randomized in the placebo group received equal volume of saline. Efficacy was evaluated by neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scales. Quality of Life was measured by EuroQoL (EQ-5D) and stroke specific quality-of-life (SS-QoL). Results: Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Number of patients receiving investigational drug within 20 hours of onset of stroke were 14/18 in saline and 10/18 in sovateltide cohorts. The baseline characteristics and SOC in both cohorts was similar. Sovateltide treatment resulted in a significantly quicker recovery as measured by improvements in neurological outcomes in mRS and BI scales on day 6 compared to day 1 (p<0.0001). Moreover, sovateltide increased the frequency of favorable outcomes in all scales at 3 months. An improvement of ≥2 points in mRS was observed in 60% and 40% patients in sovateltide and saline groups, respectively (p=0.0519; odds ratio 5.25). BI improvement of ≥40 points was 64% and 36% in sovateltide and saline groups, respectively (p=0.0112; odds ratio 12.44). An improvement of ≥6 points was seen in NIHSS in 56% of patients in sovateltide vs 43% in saline groups (p=0.2714; odds ratio 2.275). Number of patients with complete recovery achieving NIHSS score of 0 and BI of 100 were significantly more (p<0.05) in sovateltide group compared to saline group. Sovateltide treatment resulted in improved Quality of Life as measured by EuroQoL and SS-QoL (stroke specific quality-of-life) on day 90. Sovateltide was well tolerated and all patients received complete treatment with no incidence of drug related adverse event reported. Hemodynamic, biochemical or hematological parameters were not affected with sovateltide. Conclusion: Sovateltide was safe, well tolerated, and resulted in quicker recovery and improved neurological outcome in acute cerebral ischemic stroke patients 90 days post-treatment.

Sign in / Sign up

Export Citation Format

Share Document