Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease

Abstract

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD.

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…Recently, Sato et al also demonstrated that IS potentiated mitochondrial dysfunction as well as our study. In addition, a significant inverse association between plasma IS levels and skeletal muscle mass in patients with CKD was observed 44. The data suggest that IS is a pathogenic factor for muscle atrophy in the patients with CKD.…”

“…In addition, a significant inverse association between plasma IS levels and skeletal muscle mass in patients with CKD was observed. 44 The data suggest that IS is a pathogenic factor for muscle atrophy in the patients with CKD. However, the clinical data reported by Sato et al were a correlation study and, as a result, would not have the same relevance as would be obtained in a large randomized study.…”

Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS–based metabolomics approach

“…Our findings revealed that microbiota metabolism is completely responsible for the accumulation of indoxyl sulfate and p-cresyl sulfate, which are the major uremic toxins involved in the progression of CKD, cardiovascular disease, and muscle loss. 6,27 Additionally, of the M-USs, TMAO increases the risk of cardiovascular disease via its potent proatherosclerotic and prothrombotic effects. 28 Dimethylglycine has also been associated with an increased risk of cardiovascular disease.…”

Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis

“…While these findings implicate LPS and inflammation as causative agents in the process, inflammation-independent alterations in skeletal muscle metabolism have also been observed. For example, in response to the gut microbiota-specific metabolite indoxyl sulfate [38], C2C12 myoblasts exhibit an up-regulation of glycolysis and an increase in the activity of the pentose phosphate pathway [39]. Similarly, exposure of myotubes to gut microbial-derived extracellular vesicles induces insulin resistance [30], highlighting the multitude of ways in which gut microbiota may influence the metabolic function of skeletal muscle.…”