Exercise Is Associated with Skeletal Muscle Autophagy–Lysosome-Related Markers and Nrf2/ARF1 Signaling in HFD Mice
- 1School of Education and Physical Education, Yangtze University, Jingzhou 434023, China
- 2Department of Biochemistry and Molecular Biology, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
Abstract
Purpose: This study aimed to investigate the protective effects and potential mechanisms of exercise against long-term high-fat diet (HFD)-induced skeletal muscle dysfunction, with a focus on ADP-ribosylation factor 1 (ARF1)-related autophagy–lysosome markers and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Methods: Forty male C57BL/6 mice were randomly divided into a normal diet group (DC) and an HFD group, and the latter was further subdivided into a model group (MG), exercise group (EG), Nrf2 inhibitor group (NG), and exercise combined with Nrf2 inhibitor group (ENG) after 12 weeks of HFD feeding. EG received 6 weeks of moderate-intensity treadmill exercise, NG was treated with Nrf2 inhibitor for 6 weeks, and ENG received both the 6-week treadmill exercise and inhibitor injections simultaneously. Serum lipid, blood glucose and insulin resistance indices were detected; skeletal muscle morphology was observed by H&E staining; mRNA and protein expression of ARF1, ULK1, ATP6V0A1 and other factors were determined by RT-qPCR, Western blotting and immunohistochemistry; the oxidative stress index was measured by an ELISA; and the colocalization of ARF1/ATP6V0A1 with the lysosomal marker Lamp1 was analyzed by immunofluorescence. Results: Long-term HFD significantly increased mouse body weight, serum TC, TG, LDL-C, FBG levels and the HOMA-IR index, induced morphological alterations in skeletal muscle (loose myofiber arrangement, abundant intracellular vacuoles), inhibited the mRNA expression of ARF1, ULK1 and ATP6V0A1, and elevated malondialdehyde (MDA) content (p < 0.05 or p < 0.01). Six weeks of moderate-intensity treadmill exercise effectively improved HFD-induced metabolic disorders and skeletal muscle morphological damage, upregulated the expression of ARF1, ULK1 and ATP6V0A1, and reduced oxidative stress (p < 0.05 or p < 0.01). Notably, luteolin-mediated inhibition of Nrf2 signaling may partially reverse exercise-induced alterations in ARF1-related autophagy–lysosome markers and skeletal muscle morphology. Conclusions: Long-term HFD may induce morphological alterations in skeletal muscle, accompanied by changes in ARF1-associated autophagy–lysosome markers and elevated oxidative stress. Conversely, moderate-intensity exercise may ameliorate HFD-related changes in skeletal muscle morphology, potentially via Nrf2 signaling, providing a potential molecular target and theoretical basis for the exercise intervention strategies against HFD-induced metabolic-related skeletal muscle dysfunction.
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BibTeX
@article{hu2026exercise,
title = {{Exercise Is Associated with Skeletal Muscle Autophagy–Lysosome-Related Markers and Nrf2/ARF1 Signaling in HFD Mice}},
author = {Shujuan Hu and Xuan Liu and Ruohan Xia and Xianwang Wang},
journal = {Nutrients},
year = {2026},
month = oct,
doi = {10.3390/nu18203329},
url = {https://www.mdpi.com/2072-6643/18/20/3329},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exercise Is Associated with Skeletal Muscle Autophagy–Lysosome-Related Markers and Nrf2/ARF1 Signaling in HFD Mice
AU - Shujuan Hu
AU - Xuan Liu
AU - Ruohan Xia
AU - Xianwang Wang
PY - 2026
DA - 2026/10/01
JO - Nutrients
DO - 10.3390/nu18203329
UR - https://www.mdpi.com/2072-6643/18/20/3329
AB - Purpose: This study aimed to investigate the protective effects and potential mechanisms of exercise against long-term high-fat diet (HFD)-induced skeletal muscle dysfunction, with a focus on ADP-ribosylation factor 1 (ARF1)-related autophagy–lysosome markers and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Methods: Forty male C57BL/6 mice were randomly divided into a normal diet group (DC) and an HFD group, and the latter was further subdivided into a model group (MG), exercise group (EG), Nrf2 inhibitor group (NG), and exercise combined with Nrf2 inhibitor group (ENG) after 12 weeks of HFD feeding. EG received 6 weeks of moderate-intensity treadmill exercise, NG was treated with Nrf2 inhibitor for 6 weeks, and ENG received both the 6-week treadmill exercise and inhibitor injections simultaneously. Serum lipid, blood glucose and insulin resistance indices were detected; skeletal muscle morphology was observed by H&E staining; mRNA and protein expression of ARF1, ULK1, ATP6V0A1 and other factors were determined by RT-qPCR, Western blotting and immunohistochemistry; the oxidative stress index was measured by an ELISA; and the colocalization of ARF1/ATP6V0A1 with the lysosomal marker Lamp1 was analyzed by immunofluorescence. Results: Long-term HFD significantly increased mouse body weight, serum TC, TG, LDL-C, FBG levels and the HOMA-IR index, induced morphological alterations in skeletal muscle (loose myofiber arrangement, abundant intracellular vacuoles), inhibited the mRNA expression of ARF1, ULK1 and ATP6V0A1, and elevated malondialdehyde (MDA) content (p < 0.05 or p < 0.01). Six weeks of moderate-intensity treadmill exercise effectively improved HFD-induced metabolic disorders and skeletal muscle morphological damage, upregulated the expression of ARF1, ULK1 and ATP6V0A1, and reduced oxidative stress (p < 0.05 or p < 0.01). Notably, luteolin-mediated inhibition of Nrf2 signaling may partially reverse exercise-induced alterations in ARF1-related autophagy–lysosome markers and skeletal muscle morphology. Conclusions: Long-term HFD may induce morphological alterations in skeletal muscle, accompanied by changes in ARF1-associated autophagy–lysosome markers and elevated oxidative stress. Conversely, moderate-intensity exercise may ameliorate HFD-related changes in skeletal muscle morphology, potentially via Nrf2 signaling, providing a potential molecular target and theoretical basis for the exercise intervention strategies against HFD-induced metabolic-related skeletal muscle dysfunction.
SN - 2072-6643
ER -