Abstract
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.
Highlights
A cerebral vascular accident or stroke is described as a sudden interruption in the blood supply of the brain as a result of either an abrupt blockage of arteries leading to the brain or bleeding into brain tissue when a blood vessel bursts
To determine the genome-wide transcriptome profile of post-stroke skeletal muscle, we first induced cerebral ischemic stroke for 45 min using the middle cerebral artery occlusion (MCAO) method in mice. 45’MCAO followed by 72 h reperfusion significantly caused ~40% brain lesion in the lateral striatum and parietal cortex regions (Figure 1A,B), which severely induced motor deficit as evidenced by higher neurological score (Figure 1C)
To determine if loss of motor function could lead to muscle atrophy and weakness, we measured paralytic tibialis anterior (PTA) muscle mass, which was notably lower in MCAO mice compared to the corresponding tibialis anterior (CTA) muscle of sham mice (Figure 1E)
Summary
A cerebral vascular accident or stroke is described as a sudden interruption in the blood supply of the brain as a result of either an abrupt blockage of arteries leading to the brain (ischemic stroke) or bleeding into brain tissue when a blood vessel bursts (hemorrhagic stroke). Health Organization, stroke results in five million deaths worldwide each year, and ischemic stroke accounts for 87% of all stroke incidents [1]. An additional five million stroke patients will experience long-term disability, reducing quality of life while contributing to the international. In the United States, stroke is the fifth most common cause of death and a leading cause of long-term disability in patients [2]. In the United States, stroke affects nearly 800,000 individuals annually, and ~75% of these are first-ever strokes, whereas the remaining 25% are recurrent strokes [2]. Stroke is often viewed as a disease of the elderly, it can occur at any age; ~10% of all strokes occur in individuals aged between 18 and 50 years [2]
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