Endothelin-1-mediated miR-let-7g-5p triggers interlukin-6 and TNF-α to cause myopathy and chronic adipose inflammation in elderly patients with diabetes mellitus

Abstract

Background: Diabetes and sarcopenia are verified as mutual relationships, which seriously affect the quality of life of the elderly. Endothelin-1 is well investigated, is elevated in patients with diabetes, and is related to muscle cellular senescence and fibrosis. However, the mechanism of ET-1 between diabetes and myopathy is still unclear. The aim of this study was to evaluate the prevalence of sarcopenia in the elderly with diabetes and to clarify its relationship with ET-1 molecular biological mechanism, progress as well as changes in muscle and fat. Methods: We recruited 157 type 2 diabetes patients over 55 years old and investigated the prevalence of sarcopenia in diabetes patients and examined the association of ET-1 alterations with HbA1c, creatinine, or AMS/ht2. Next, sought to determine how ET-1 regulates inflammation in muscle cells by western blot and qPCR assay. Using XF Seahorse Technology, we directly quantified mitochondrial bioenergetics in 3T3-L1 cells. Results: ET-1 was positively correlated with HbA1c, creatinine levels, and duration of disease, and negatively correlated with AMS/ht2. We found that ET-1 dose-dependently induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6β expression through the PI3K/AKT, and NF-κB signaling pathways in C2C12 cells. Also identified that TNF-α, IL-6β, and visfatin releases were found in co-cultured with conditioned medium of ET-1/C2C12 in 3T3-L1 cells. ET-1 also reduces the energy metabolism of fat and induces micro-environment inflammation which causes myopathy. ET-1 also suppresses miR-let-7g-5p expression in myocytes and adipocytes. Conclusion: We describe a new mechanism of ET-1 triggering chronic inflammation in patients with hyperglycemia.

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

“…miR-let-7g-5p expression is suppressed by ET-1 (endothelin-1), subsequently leading to increased TNF-α and IL-6 expression in a dose-dependent manner. This suppression of miR-let-7g-5p contributes to reduced fat metabolism and increases inflammation, promoting myopathy[ 37 ]. Taylor et al [ 38 ] identified 84 heritable miRNAs and 5 miRNA-expression (miR-216a, miR-25, miR-30a-3p, and miR-30a-5p) quantitative trait loci associated with blood glucose and glycated HbA1c levels.…”

The Association Between Sarcopenia and Diabetes: From Pathophysiology Mechanism to Therapeutic Strategy

“… 162 Endothelin-1 (ET-1) may play a critical role in mediating myopathy and adipose inflammation through the release of IL-6, TNF-α, or adipokines, visfatin, which involve PI3K/Akt/miR-let-7g-5p pathways in elderly individuals with diabetes. 163 These findings can promote conceptualization and development of novel approaches or strategies for sarcopenia and with its related diseases in the future.…”

Sarcopenia and noncoding RNAs: A comprehensive review

“…Activation of this pathway contributes to the upregulation of miR‐let‐7d‐3p, resulting in inhibition of HMGA2 and muscular stem cell proliferation in aged mice (Itokazu et al, 2022). In aged diabetic patients and C2C12 cells, upregulation of miR‐let‐7g‐5p induces muscle atrophy through inflammation with the help of tumor necrosis factor‐α/interleukin‐6 (IL6) (Tsai et al, 2022).…”