Tomoaki Shirakawa_No.4

Q: How did the anthor address the question?

■Step1 RIC improves MASH Chronic remote limb ischemic conditioning was performed in mice with established MASH. RIC improved hepatic steatosis, inflammation, and fibrosis in multiple diet-induced MASH models. RNA-seq analysis also showed improvement of MASH-associated transcriptomic abnormalities in the liver. ■Step2 Identification of the muscle-to-liver sEV–miR-181d-5p–NR4A3 axis The hepatoprotective effect of RIC was mediated by miR-181d-5p carried to the liver by skeletal muscle-derived small extracellular vesicles. Overexpression of miR-181d-5p in hepatocytes reproduced the beneficial effects of RIC on MASH, and these effects were mediated through suppression of NR4A3. ■Step3 Human RIC-derived EVs also reproduced the therapeutic effect Circulating EVs collected from human volunteers after RIC improved pathological phenotypes and transcriptomic changes in MASH mice and primary human hepatocytes. These findings suggest that the muscle–liver crosstalk identified in mice may also be relevant in humans.

kawaokashinpei3

4 days ago

2 min read

Selected journal : Cell Metabolism

Remote limb ischemic conditioning alleviates steatohepatitis via extracellular vesicle-mediated muscle-liver crosstalk

https://pubmed.ncbi.nlm.nih.gov/40118054/

What is the main question of the paper?

Can remote limb ischemic conditioning improve MASH through muscle-to-liver communication, and what molecular mechanism mediates this effect?

How did the anthor address the question?

■Step1

RIC improves MASH

Chronic remote limb ischemic conditioning was performed in mice with established MASH. RIC improved hepatic steatosis, inflammation, and fibrosis in multiple diet-induced MASH models. RNA-seq analysis also showed improvement of MASH-associated transcriptomic abnormalities in the liver.

■Step2

Identification of the muscle-to-liver sEV–miR-181d-5p–NR4A3 axis

The hepatoprotective effect of RIC was mediated by miR-181d-5p carried to the liver by skeletal muscle-derived small extracellular vesicles. Overexpression of miR-181d-5p in hepatocytes reproduced the beneficial effects of RIC on MASH, and these effects were mediated through suppression of NR4A3.

■Step3

Human RIC-derived EVs also reproduced the therapeutic effect

Circulating EVs collected from human volunteers after RIC improved pathological phenotypes and transcriptomic changes in MASH mice and primary human hepatocytes. These findings suggest that the muscle–liver crosstalk identified in mice may also be relevant in humans.

What is the strength of the paper?

I think the strength of this paper is that it starts from the unexpected finding that RIC improves MASH and then gradually narrows down the mechanism to muscle-derived EVs, miR-181d-5p, and NR4A3, while showing causality at each step. Furthermore, by reproducing the effect using EVs from humans after RIC, the authors showed that the mechanism identified in mice may also be applicable to humans.

Comment

This study revealed a novel muscle-liver metabolic crosstalk in which small extracellular vesicles released from skeletal muscle in response to ischemic stimulation of the limbs transport miR-181d-5p to the liver and improve MASH by suppressing NR4A3. What I find particularly impressive is the seamless progression from the discovery of the phenomenon → demonstration of inter-organ signaling → identification of the carrier → identification of the cargo → identification of the target → loss-of-function/gain-of-function studies → translation to humans.

Comment by Yuki Nakamura