Stroke survivors often face complications that hinder recovery and reduce quality of life. These complications include weight loss (or cachexia) and muscle wasting (or sarcopenia), which are both linked to poor stroke outcomes. While cachexia and sarcopenia are well documented in other clinical conditions such as cancer and heart failure, their prevalence and underlying mechanisms in stroke remain largely unexplored. Some obvious factors that may contribute to post-stroke weight and muscle loss include impaired feeding and malnutrition, paresis and physical inactivity. Preclinical studies have shown that experimental stroke induces marked weight loss in rodents, which involves global wasting of lean and fat tissue. As such, it has been hypothesised that post-stroke weight loss and muscle wasting arise from catabolic overactivation and anabolic blunting driven at least in part by systemic pathophysiological mechanisms triggered by the ischaemic insult. Such systemic pathophysiological mechanisms include inflammation and sympathetic activation, which are both known to alter catabolic and anabolic balance. Importantly, however, the relationship between ischaemic infarct and post-stroke weight loss remains unclear, and it is unclear whether the weight loss is induced by these systemic responses triggered by stroke or by secondary factors. The overarching aim of this thesis is to address key knowledge gaps regarding post-stroke weight loss and muscle wasting. Firstly, it was hypothesised that post-stroke weight loss and sarcopenia are under appreciated complications but are prevalent within the stroke population. Secondly, it was hypothesised that post-stroke weight loss in pre-clinical stroke models is dictated by stroke severity and/or the anatomical location of the infarct supporting the notion that mechanisms triggered by the brain injury contribute to body weight loss. Finally, it was hypothesised that stroke leads to an upregulation of genes in skeletal muscle involved in the catabolic pathway and a downregulation of genes involved in protein synthesis and anabolic pathways, contributing to muscle wasting. In this thesis, the systematic review and meta-analysis of clinical studies demonstrate that the pooled prevalence of post-stroke weight loss and stroke-related sarcopenia is 31% and 36% respectively, among stroke survivors. Furthermore, both conditions were linked to poor clinical and functional outcomes, and a more extended hospital stay. Our preclinical data using the middle cerebral artery occlusion (MCAo) and photothrombotic (PT) models found that profound weight loss occurred in the acute phase after stroke, which was characterised by marked visceral fat loss, and skeletal muscle loss in both hindlimbs (stroke-affected and non-affected side) of mice. Importantly, water and food intake did not differ significantly between stroke and sham mice, suggesting that reduced food or water consumption alone is insufficient to explain weight loss after experimental stroke. Our data subsequently found a significant, moderate positive correlation between infarct volume and weight loss, indicating that larger infarcts are associated with greater weight reduction. Furthermore, in exploratory analyses, no association was found between infarct location and weight loss, suggesting that lesion size, rather than its anatomical position, is a determinant of the extent of post-stroke weight loss. Using non-targeted metabolomics, we next assessed the metabolic response to stroke in young and aged mice. Multivariate and univariate analyses revealed no differences among sham or stroke mice and between the age groups. However, using a linear model we found potential stroke-associated metabolic alterations in metabolites involved in lipid, fatty acid, and tryptophan metabolism. Finally, we found that weight loss in mice after experimental stroke (transient MCAo tMCAo) persisted up to ~21 days after stroke onset whereas the loss of skeletal muscle mass was evident only of days 3 and 7 post-stroke induction. Furthermore, the loss of skeletal mass after experimental stroke (transient MCAo) in young and aged mice was associated with upregulation of catabolic genes (e.g., MuRF-1) in the acute phase after stroke, consistent with gene expression patterns observed in age-related sarcopenia. Lastly, there was evidence for increased gene expression of the pro-inflammatory cytokine TNF-α in the skeletal muscle of both hindlimbs supporting the potential involvement of inflammatory mechanisms in post-stroke muscle wasting. In conclusion, this thesis demonstrates that post-stroke weight loss or muscle wasting are prevalent in the stroke population, and our pre-clinical work suggests that this may be dictated, at least in part, by stroke severity. These findings indicate that post-stroke weight and muscle loss is a multifactorial and complex process, underscoring the importance of recognising and addressing these conditions as a significant clinical issue after stroke and highlighting the need for more studies to target systemic mechanisms to better understand mechanisms and improve recovery.
Jawzaa Alenazi (Thu,) studied this question.