Exercise (HIIT) enhances hepatic mitochondrial structure and function while preventing endoplasmic reticulum stress and MASLD in HF-fed mice

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increasing attention from the scientific community due to its severe but silent progression and the lack of specific treatment. Glucolipotoxicity triggers endoplasmic reticulum (ER) stress with decreased beta-oxidation and enhanced lipogenesis, promoting the onset of MASLD, whereas regular physical exercise can prevent MASLD by preserving ER and mitochondrial function. Thus, the hypothesis of this study was that high-intensity interval training (HIIT) could prevent the development of MASLD in HF-fed C57BL/6J mice by maintaining insulin sensitivity, preventing ER stress, and promoting beta-oxidation. Forty male C57BL/6J mice (3 months old) comprised four experimental groups: the control (C) diet group, the C diet + HIIT (C-HIIT) group, the high-fat (HF) diet group, and the HF diet + HIIT (HF-HIIT) group. HIIT sessions lasted 12 minutes and were performed thrice weekly by trained mice. The diet and exercise protocols lasted for ten weeks. The HIIT protocol prevented weight gain and maintained insulin sensitivity in the HF-HIIT group. A chronic HF diet increased ER stress-related gene and protein expression, but HIIT helped to maintain ER homeostasis, preserve mitochondrial ultrastructure, and maximize beta-oxidation. The increased sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (Sirt1/Pgc1a) expression implies that HIIT enhanced mitochondrial biogenesis and yielded adequate mitochondrial dynamics. High hepatic fibronectin type III domain containing 5 (Fndc5)/irisin agreed with the anti-lipogenic and anti-inflammatory effects observed in the HF-HIIT group, reinforcing the anti-steatotic effects of HIIT. Thus, we confirmed that practicing HIIT, three times a week, maintained insulin sensitivity, prevented ER stress, and enhanced hepatic beta-oxidation, impeding MASLD development in this mouse model even when consuming high energy intake from saturated fatty acids.