Effect of cardiovascular-kidney-metabolic syndrome on murine skeletal muscle
Embargo Date
2028-02-26
OA Version
Citation
Abstract
Cardiovascular-Kidney-Metabolic (CKM) syndrome is a highly prevalent condition that is comprised of common diseases such as cardiovascular disease, chronic kidney disease (CKD), and type 2 diabetes mellitus. In clinical settings, patients with CKM often present with sarcopenia. Given the role of proteasomes in protein degradation, we sought to understand how proteasome activity and expression changes in the setting of CKM. We used mouse models of CKD, obesity, and CKM to elucidate how certain metabolic conditions may differentially affect the proteasome. Additionally, given the function of uremic toxins in the pathogenesis of CKD, we treated mice with Indoxyl Sulfate (IS), to understand how a uremic milieu might specifically alter proteasome function and constitution. We found that there was a sex-specific change in the proteasome’s chymotrypsin-like (CTL) activity in the presence of IS, such that females mice treated with IS showed lower CTL activity than control female mice. We also found that un-normalized proteasome activity did not change in the setting of metabolic diseases like CKM and CKD. Further work is needed to normalize the proteasome activity to proteasome expression. Notably, proteasome subtype expression showed drastic changes, but the expected activity change that would accompany this class-switching was absent. This suggests that proteasome activity was reduced despite an increase in proteasome expression. Ultimately, our findings indicate that metabolic conditions and uremic milieu alter proteasome activity and expression.
Description
2025