Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Br J Pharmacol. 2022 Jan;179(1):159-178. doi: 10.1111/bph.15693. Epub 2021 Nov 23.
Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking loss of muscle proteins, which increases morbidity and mortality risks. Evidence shows that short-chain fatty acids (SCFAs) play an important role in health maintenance and disease development. Recently, the connection between butyrate (a SCFA) and DN has been revealed, although the relationship between butyrate and muscle atrophy remains unclear.
We studied changes in serum butyrate levels in DN patients using metabolomic analyses. In db/db mice, protective effects of butyrate on DN-induced muscle atrophy. were explored. Inhibition of muscle atrophy by butyrate and the underlying mechanism(s) were studied in C2C12 cells exposed to high glucose/lipopolysaccharide (HG/LPS).
Butyrate levels in DN patients were significantly decreased. In db/db mice, supplementing normal diet with butyrate improved intestinal barrier function. Concurrently, butyrate alleviated muscle atrophy, promoted PI3K/Akt/mTOR signalling, and suppressed oxidative stress and autophagy in skeletal muscle of db/db mice, and in HG/LPS-exposed C2C12 cells. Further, FFA2 receptors, key components of SCFA signalling, were decreased in skeletal muscle of db/db mice and in HG/LPS-exposed C2C12 cells. Overexpression of FFA2 receptors activated PI3K/Akt/mTOR signalling and inhibited oxidative stress and autophagy in HG/LPS-exposed C2C12 cells. Silencing of FFA2 blocked PI3K/Akt/mTOR signalling that was improved by butyrate, as well as the suppression of oxidative stress and reduction of autophagy.
Butyrate exerts protective effects on muscle atrophy induced by DN by enhancing intestinal barrier function and activating the FFA2 receptor-mediated PI3K/Akt/mTOR pathway.
糖尿病肾病（DN）患者的肌肉蛋白分解导致肌肉蛋白大量丢失，增加了发病率和死亡率风险。有证据表明，短链脂肪酸（SCFAs）在维持健康和疾病发展中起着重要作用。最近，丁酸（一种 SCFA）与 DN 之间的联系已经被揭示，尽管丁酸与肌肉萎缩之间的关系尚不清楚。
我们使用代谢组学分析研究了 DN 患者血清丁酸水平的变化。在 db/db 小鼠中，研究了丁酸对 DN 诱导的肌肉萎缩的保护作用。在高糖/脂多糖（HG/LPS）暴露的 C2C12 细胞中，研究了丁酸对肌肉萎缩的抑制作用及其潜在机制。
DN 患者的丁酸水平显著降低。在 db/db 小鼠中，在正常饮食中补充丁酸可改善肠道屏障功能。同时，丁酸缓解了 db/db 小鼠骨骼肌的萎缩，促进了 PI3K/Akt/mTOR 信号通路，并抑制了骨骼肌的氧化应激和自噬，以及 HG/LPS 暴露的 C2C12 细胞。此外，FFA2 受体，SCFA 信号的关键组成部分，在 db/db 小鼠和 HG/LPS 暴露的 C2C12 细胞中的骨骼肌中减少。FFA2 受体的过表达激活了 PI3K/Akt/mTOR 信号通路，并抑制了 HG/LPS 暴露的 C2C12 细胞中的氧化应激和自噬。FFA2 沉默阻断了丁酸改善的 PI3K/Akt/mTOR 信号通路，以及氧化应激的抑制和自噬的减少。
丁酸通过增强肠道屏障功能和激活 FFA2 受体介导的 PI3K/Akt/mTOR 通路，对 DN 诱导的肌肉萎缩发挥保护作用。
