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

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

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

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

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

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

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

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

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

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Fenping ZhengDepartment 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
Restricted access

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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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Print ISSN:
0952-5041
Online ISSN:
1479-6813
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

  • Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y & & Dynlacht BD 2007 XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Molecular Cell 27 53–66. (https://doi.org/10.1016/j.molcel.2007.06.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Afroze D & & Kumar A 2019 ER stress in skeletal muscle remodeling and myopathies. FEBS Journal 286 379–398. (https://doi.org/10.1111/febs.14358)

  • Allen DL & & Leinwand LA 2002 Intracellular calcium and myosin isoform transitions. Calcineurin and calcium-calmodulin kinase pathways regulate preferential activation of the IIa myosin heavy chain promoter. Journal of Biological Chemistry 277 45323–45330. (https://doi.org/10.1074/jbc.M208302200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bahar E, Kim H & & Yoon H 2016 ER stress-mediated signaling: action potential and Ca(2+) as key players. International Journal of Molecular Sciences 17 1558. (https://doi.org/10.3390/ijms17091558)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bamman MM, Roberts BM & & Adams GR 2018 Molecular regulation of exercise-induced muscle fiber hypertrophy. Cold Spring Harbor Perspectives in Medicine 8 a029751. (https://doi.org/10.1101/cshperspect.a029751)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bishop-Bailey D 2013 Mechanisms governing the health and performance benefits of exercise. British Journal of Pharmacology 170 1153–1166. (https://doi.org/10.1111/bph.12399)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bohnert KR, Gallot YS, Sato S, Xiong G, Hindi SM & & Kumar A 2016 Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. FASEB Journal 30 3053–3068. (https://doi.org/10.1096/fj.201600250RR)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bohnert KR, Mcmillan JD & & Kumar A 2018 Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. Journal of Cellular Physiology 233 67–78. (https://doi.org/10.1002/jcp.25852)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Booth FW, Ruegsegger GN, Toedebusch RG & & Yan Z 2015 Endurance exercise and the regulation of skeletal muscle metabolism. Progress in Molecular Biology and Translational Science 135 129–151. (https://doi.org/10.1016/bs.pmbts.2015.07.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chang JH, Lin KH, Shih CH, Chang YJ, Chi HC & & Chen SL 2006 Myogenic basic helix-loop-helix proteins regulate the expression of peroxisomal proliferator activated receptor-gamma coactivator-1alpha. Endocrinology 147 3093–3106. (https://doi.org/10.1210/en.2005-1317)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dekki N, Refai E, Holmberg R, Kohler M, Jornvall H, Berggren PO & & Juntti-Berggren L 2012 Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic beta-cell. Cellular and Molecular Life Sciences 69 1733–1743. (https://doi.org/10.1007/s00018-011-0899-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gallot YS, Bohnert KR, Straughn AR, Xiong G, Hindi SM & & Kumar A 2019 PERK regulates skeletal muscle mass and contractile function in adult mice. FASEB Journal 33 1946–1962. (https://doi.org/10.1096/fj.201800683RR)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Guo S, Huang Y, Zhang Y, Huang H, Hong S & & Liu T 2020 Impacts of exercise interventions on different diseases and organ functions in mice. Journal of Sport and Health Science 9 53–73. (https://doi.org/10.1016/j.jshs.2019.07.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gurd BJ, Menezes ES, Arhen BB & & Islam H 2022 Impacts of altered exercise volume, intensity, and duration on the activation of AMPK and CaMKII and increases in PGC1αlpha mRNA. Seminars in Cell and Development Biology 143 17–27.

    • Search Google Scholar
    • Export Citation

  • Handschin C 2010 Regulation of skeletal muscle cell plasticity by the peroxisome proliferator-activated receptor gamma coactivator 1alpha. Journal of Receptor and Signal Transduction Research 30 376–384. (https://doi.org/10.3109/10799891003641074)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z & & Spiegelman BM 2007 Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC1α muscle-specific knock-out animals. Journal of Biological Chemistry 282 30014–30021. (https://doi.org/10.1074/jbc.M704817200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hawley JA, Lundby C, Cotter JD & & Burke LM 2018 Maximizing cellular adaptation to endurance exercise in skeletal muscle. Cell Metabolism 27 962–976. (https://doi.org/10.1016/j.cmet.2018.04.014)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • He Y, Qiu R, Wu B, Gui W, Lin X, Li H & & Zheng F 2021 Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism 320 E808–E821. (https://doi.org/10.1152/ajpendo.00495.2020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hickey MS, Carey JO, Azevedo JL, Houmard JA, Pories WJ, Israel RG & & Dohm GL 1995 Skeletal muscle fiber composition is related to adiposity and in vitro glucose transport rate in humans. American Journal of Physiology 268 E453–E457. (https://doi.org/10.1152/ajpendo.1995.268.3.E453)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Joseph JS, Anand K, Malindisa ST & & Fagbohun OF 2021 Role of CaMKII in the regulation of fatty acids and lipid metabolism. Diabetes and Metabolic Syndrome 15 589–594. (https://doi.org/10.1016/j.dsx.2021.02.037)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Koch LG, Pollott GE & & Britton SL 2013 Selectively bred rat model system for low and high response to exercise training. Physiological Genomics 45 606–614. (https://doi.org/10.1152/physiolgenomics.00021.2013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lancel S, Hesselink MK, Woldt E, Rouillé Y, Dorchies E, Delhaye S, Duhem C, Thorel Q, Mayeuf-Louchart A, Pourcet B, et al.2018 Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity. JCI Insight 3 e98081. (https://doi.org/10.1172/jci.insight.98081)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lessard SJ, Rivas DA, Alves-Wagner AB, Hirshman MF, Gallagher IJ, Constantin-Teodosiu D, Atkins R, Greenhaff PL, Qi NR, Gustafsson T, et al.2013 Resistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks. Diabetes 62 2717–2727. (https://doi.org/10.2337/db13-0062)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li L, Pan R, Li R, Niemann B, Aurich AC, Chen Y & & Rohrbach S 2011 Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required. Diabetes 60 157–167. (https://doi.org/10.2337/db10-0331)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lim S, Choi SH, Jeong IK, Kim JH, Moon MK, Park KS, Lee HK, Kim YB & & Jang HC 2008 Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. Journal of Clinical Endocrinology and Metabolism 93 2263–2268. (https://doi.org/10.1210/jc.2007-2028)

    • Search Google Scholar
    • Export Citation

  • Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, et al.2002 Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418 797–801. (https://doi.org/10.1038/nature00904)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mallinson J, Meissner J & & Chang KC 2009. Chapter 2 Calcineurin signaling and the slow oxidative skeletal muscle fiber type. International Review of Cell and Molecular Biology 277 67–101.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marafon BB, Pinto AP, Ropelle ER, De Moura LP, Cintra DE, Pauli JR & & Da Silva ASR 2022 Muscle endoplasmic reticulum stress in exercise. Acta Physiologica (Oxford, England) 235 e13799. (https://doi.org/10.1111/apha.13799)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mukwevho E & & Joseph JS 2014 Calmodulin dependent protein kinase II activation by exercise regulates saturated & unsaturated fatty acids and improves some metabolic syndrome markers. Life Sciences 111 53–61. (https://doi.org/10.1016/j.lfs.2014.07.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Oberbach A, Bossenz Y, Lehmann S, Niebauer J, Adams V, Paschke R, Schon MR, Bluher M & & Punkt K 2006 Altered fiber distribution and fiber-specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes. Diabetes Care 29 895–900. (https://doi.org/10.2337/diacare.29.04.06.dc05-1854)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pedersen BK & & Saltin B 2015 Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases. Scandinavian Journal of Medicine and Science in Sports 25(Supplement 3) 1–72. (https://doi.org/10.1111/sms.12581)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Powers SK 2017 Exercise: teaching myocytes new tricks. Journal of Applied Physiology 123 460–472. (https://doi.org/10.1152/japplphysiol.00418.2017)

  • Rasbach KA, Gupta RK, Ruas JL, Wu J, Naseri E, Estall JL & & Spiegelman BM 2010 PGC1αlpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. PNAS 107 21866–21871. (https://doi.org/10.1073/pnas.1016089107)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rowe GC, Safdar A & & Arany Z 2014 Running forward: new frontiers in endurance exercise biology. Circulation 129 798–810. (https://doi.org/10.1161/CIRCULATIONAHA.113.001590)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, et al.2003 Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 52 2874–2881. (https://doi.org/10.2337/diabetes.52.12.2874)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Simoneau JA, Veerkamp JH, Turcotte LP & & Kelley DE 1999 Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB Journal 13 2051–2060. (https://doi.org/10.1096/fasebj.13.14.2051)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stuart CA, Mccurry MP, Marino A, South MA, Howell ME, Layne AS, Ramsey MW & & Stone MH 2013 Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness. Journal of Clinical Endocrinology and Metabolism 98 2027–2036. (https://doi.org/10.1210/jc.2012-3876)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tanner CJ, Barakat HA, Dohm GL, Pories WJ, Macdonald KG, Cunningham PR, Swanson MS & & Houmard JA 2002 Muscle fiber type is associated with obesity and weight loss. American Journal of Physiology. Endocrinology and Metabolism 282 E1191–E1196. (https://doi.org/10.1152/ajpendo.00416.2001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Boström P, Tyra HM, Crawford RW, Campbell KP, et al.2011 The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metabolism 13 160–169. (https://doi.org/10.1016/j.cmet.2011.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xiong G, Hindi SM, Mann AK, Gallot YS, Bohnert KR, Cavener DR, Whittemore SR & & Kumar A 2017 The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration. eLife 6 e22871. (https://doi.org/10.7554/eLife.22871)

    • PubMed
    • Search Google Scholar
    • Export Citation