Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance

in Journal of Molecular Endocrinology
Authors:
Beibei Wu Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Ruojun Qiu Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Shuo Wang Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Yingzi He Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Jing Wang Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Zhiye Xu Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Xihua Lin Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Hong Li Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Fenping Zheng Department of Endocrinology of Sir Run Run Shaw Hospital affiliated to Medical School of Zhejiang University, Hangzhou, Zhejiang, China

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Correspondence should be addressed to F Zheng: 3407004@zju.edu.cn

*(B Wu and R Qiu contributed equally to this work)

DOI:
https://doi.org/10.1530/JME-22-0163
Volume/Issue:
Volume 71: Issue 1
Article Type:
Research Article
Article ID:
e220163
Online Publication Date:
18 May 2023
Copyright:
© the author(s) 2023
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Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.

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Sept 2018 onwards Past Year Past 30 Days
Full Text Views 237 42 4
PDF Downloads 179 44 8

 

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© the author(s) 2023
Article ID:
e220163
Article Type:
Research Article
Received Date:
13 Feb 2023
Accepted Date:
22 Mar 2023
Print Publication Date:
01 Jul 2023
Online Publication Date:
18 May 2023
Keywords:
transthyretin; exercise; insulin resistance; Ca2+-dependent signaling; PGC1α; UPR

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