Maternal exercise intergenerationally drives muscle-based thermogenesis via activation of apelin-AMPK signaling

Jun Seok Son; Song Ah Chae; Liang Zhao; Hongyang Wang; Jeanene M. de Avila; Mei-Jun Zhu; Zhihua Jiang; Min Du

EBioMedicine (Feb 2022)

Maternal exercise intergenerationally drives muscle-based thermogenesis via activation of apelin-AMPK signaling

Jun Seok Son,
Song Ah Chae,
Liang Zhao,
Hongyang Wang,
Jeanene M. de Avila,
Mei-Jun Zhu,
Zhihua Jiang,
Min Du

Affiliations

Jun Seok Son: Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Corresponding authors.
Song Ah Chae: Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Liang Zhao: Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Hongyang Wang: Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
Jeanene M. de Avila: Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Mei-Jun Zhu: School of Food Science, Washington State University, Pullman, WA 99164, USA
Zhihua Jiang: Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Min Du: Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA; Corresponding authors.

Journal volume & issue: Vol. 76
p. 103842

Abstract

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Summary: Background: Sarcolipin and uncoupling protein 3 (UCP3) mediate muscle-based non-shivering thermogenesis (NST) to improve metabolic homeostasis. The impacts of maternal obesity (MO) and maternal exercise (ME) on NST in offspring muscle remain unexamined. Methods: Female mice were fed with a control diet or high fat diet to induce obesity. Then, obese mice were further separated into two groups: obesity only (OB) and OB plus daily exercise (OB/Ex). Fetal muscle was collected at embryonic day 18.5 and offspring mice at 3-month-old. Apelin administration during pregnancy and apelin receptor (APJ) knockout mouse were further used for investigating the mediatory role of APJ on muscle-based thermogenesis. To explore the direct effects of exercise on AMP-activated protein kinase (AMPK) downstream targets, AMPK knockout mouse was used. Findings: MO inhibited while ME activated AMPK and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in fetal muscle. AMPK activation increased sarcolipin expression, which inhibited the uptake of calcium ions into sarcoplasmic reticulum, thereby activating CaMKK2. Consistently, the expression of UCP3 and sarcolipin was suppressed due to MO but activated in ME fetal muscle. Importantly, changes of UCP3 and sarcolipin maintained in offspring muscle, showing the transgenerational effects. Furthermore, apelin administration during pregnancy mimicked the effects of ME on AMPK and CaMKK2 activation, and UCP3 and sarcolipin expression, underscoring the mediatory roles of apelin-AMPK signaling in improving fetal muscle development. Interpretation: ME, via activation of apelin signaling-AMPK axis, enhances NST gene expression in fetal and offspring muscle impaired due to MO, which intergenerationally protects offspring from diet-induced obesity and metabolic disorders. Funding: This work was supported by National Institutes of Health Grant R01-HD067449.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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