AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1

Autoři: Liwei Xiao aff001;  Jing Liu aff001;  Zongchao Sun aff001;  Yujing Yin aff001;  Yan Mao aff001;  Dengqiu Xu aff001;  Lin Liu aff001;  Zhisheng Xu aff001;  Qiqi Guo aff001;  Chenyun Ding aff001;  Wanping Sun aff001;  Likun Yang aff001;  Zheng Zhou aff001;  Danxia Zhou aff001;  Tingting Fu aff001;  Wenjing Zhou aff002;  Yuangang Zhu aff002;  Xiao-Wei Chen aff002;  John Zhong Li aff003;  Shuai Chen aff004;  Xiaoduo Xie aff005;  Zhenji Gan aff001
Působiště autorů: MOE Key Laboratory of Model Animals for Disease Study, Department of Spine Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Chemistry and Biomedicine Innovation Center (ChemBIC), Model Animal Research... aff001;  Institute of Molecular Medicine, Peking University, Beijing, China aff002;  The Key Laboratory of Rare Metabolic Disease, Department of Biochemistry and Molecular Biology, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China aff003;  MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing University, Nanjing, China aff004;  Department of Biochemistry, School of Medicine, Sun Yat-sen University, Shenzhen, China aff005
Vyšlo v časopise: AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by FNIP1. PLoS Genet 17(3): e1009488. doi:10.1371/journal.pgen.1009488
Kategorie: Research Article


Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.

Klíčová slova:

Mitochondria – Mouse models – Muscle fibers – Muscle functions – Muscle proteins – Skeletal muscle fibers – Skeletal muscles – Slow-twitch muscle fibers


1. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307(5708):384–7. Epub 2005/01/22. doi: 10.1126/science.1104343 15662004.

2. Muoio DM, Neufer PD. Lipid-induced mitochondrial stress and insulin action in muscle. Cell metabolism. 2012;15(5):595–605. Epub 2012/05/09. doi: 10.1016/j.cmet.2012.04.010 22560212; PubMed Central PMCID: PMC3348508.

3. Hesselink MK, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol. 2016;12(11):633–45. Epub 2016/07/23. doi: 10.1038/nrendo.2016.104 27448057.

4. Gan Z, Fu T, Kelly DP, Vega RB. Skeletal muscle mitochondrial remodeling in exercise and diseases. Cell Res. 2018;28(10):969–80. Epub 2018/08/16. doi: 10.1038/s41422-018-0078-7 30108290; PubMed Central PMCID: PMC6170448.

5. Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell metabolism. 2013;17(2):162–84. Epub 2013/02/12. doi: 10.1016/j.cmet.2012.12.012 23395166.

6. Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol Respir Environ Exerc Physiol. 1984;56(4):831–8. Epub 1984/04/01. doi: 10.1152/jappl.1984.56.4.831 6373687.

7. Neufer PD, Bamman MM, Muoio DM, Bouchard C, Cooper DM, Goodpaster BH, et al. Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits. Cell metabolism. 2015;22(1):4–11. Epub 2015/06/16. doi: 10.1016/j.cmet.2015.05.011 26073496.

8. Yan Z, Okutsu M, Akhtar YN, Lira VA. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. Journal of applied physiology (Bethesda, Md: 1985). 2011;110(1):264–74. Epub 2010/10/30. doi: 10.1152/japplphysiol.00993.2010 21030673; PubMed Central PMCID: PMC3253006.

9. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(25):15983–7. Epub 2002/11/22. doi: 10.1073/pnas.252625599 12444247; PubMed Central PMCID: PMC138551.

10. Lee-Young RS, Griffee SR, Lynes SE, Bracy DP, Ayala JE, McGuinness OP, et al. Skeletal muscle AMP-activated protein kinase is essential for the metabolic response to exercise in vivo. The Journal of biological chemistry. 2009;284(36):23925–34. Epub 2009/06/16. doi: 10.1074/jbc.M109.021048 19525228; PubMed Central PMCID: PMC2781986.

11. O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jorgensen SB, Schertzer JD, et al. AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(38):16092–7. Epub 2011/09/08. doi: 10.1073/pnas.1105062108 21896769; PubMed Central PMCID: PMC3179037.

12. Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008;134(3):405–15. Epub 2008/08/05. doi: 10.1016/j.cell.2008.06.051 18674809; PubMed Central PMCID: PMC2706130.

13. Garcia-Roves PM, Osler ME, Holmstrom MH, Zierath JR. Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. The Journal of biological chemistry. 2008;283(51):35724–34. Epub 2008/10/08. doi: 10.1074/jbc.M805078200 18838377.

14. Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 2006;27(7):728–35. Epub 2006/10/05. doi: 10.1210/er.2006-0037 17018837.

15. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. The Journal of clinical investigation. 2006;116(3):615–22. Epub 2006/03/03. doi: 10.1172/JCI27794 16511594; PubMed Central PMCID: PMC1386111.

16. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(29):12017–22. Epub 2007/07/05. doi: 10.1073/pnas.0705070104 17609368; PubMed Central PMCID: PMC1924552.

17. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458(7241):1056–60. Epub 2009/03/06. doi: 10.1038/nature07813 19262508; PubMed Central PMCID: PMC3616311.

18. Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(42):15552–7. Epub 2006/10/10. doi: 10.1073/pnas.0603781103 17028174; PubMed Central PMCID: PMC1592464.

19. Park H, Staehling K, Tsang M, Appleby MW, Brunkow ME, Margineantu D, et al. Disruption of Fnip1 reveals a metabolic checkpoint controlling B lymphocyte development. Immunity. 2012;36(5):769–81. Epub 2012/05/23. doi: 10.1016/j.immuni.2012.02.019 22608497; PubMed Central PMCID: PMC3361584.

20. Reyes NL, Banks GB, Tsang M, Margineantu D, Gu H, Djukovic D, et al. Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(2):424–9. Epub 2014/12/31. doi: 10.1073/pnas.1413021112 25548157; PubMed Central PMCID: PMC4299192.

21. Hasumi H, Baba M, Hasumi Y, Lang M, Huang Y, Oh HF, et al. Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(13):E1624–31. Epub 2015/03/17. doi: 10.1073/pnas.1419502112 25775561; PubMed Central PMCID: PMC4386336.

22. Siggs OM, Stockenhuber A, Deobagkar-Lele M, Bull KR, Crockford TL, Kingston BL, et al. Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(26):E3706–15. Epub 2016/06/16. doi: 10.1073/pnas.1607592113 27303042; PubMed Central PMCID: PMC4932993.

23. Ramirez JA, Iwata T, Park H, Tsang M, Kang J, Cui K, et al. Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3. J Immunol. 2019;203(11):2899–908. Epub 2019/11/05. doi: 10.4049/jimmunol.1900395 31676673; PubMed Central PMCID: PMC6864314.

24. Petit CS, Roczniak-Ferguson A, Ferguson SM. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. The Journal of cell biology. 2013;202(7):1107–22. Epub 2013/10/02. doi: 10.1083/jcb.201307084 24081491; PubMed Central PMCID: PMC3787382.

25. Liu J, Liang X, Zhou D, Lai L, Xiao L, Liu L, et al. Coupling of mitochondrial function and skeletal muscle fiber type by a miR-499/Fnip1/AMPK circuit. EMBO Mol Med. 2016;8(10):1212–28. Epub 2016/08/11. doi: 10.15252/emmm.201606372 27506764; PubMed Central PMCID: PMC5048369.

26. Sternberg EA, Spizz G, Perry WM, Vizard D, Weil T, Olson EN. Identification of upstream and intragenic regulatory elements that confer cell-type-restricted and differentiation-specific expression on the muscle creatine kinase gene. Molecular and cellular biology. 1988;8(7):2896–909. Epub 1988/07/01. doi: 10.1128/mcb.8.7.2896 3405222; PubMed Central PMCID: PMC363509.

27. Gan Z, Burkart-Hartman EM, Han DH, Finck B, Leone TC, Smith EY, et al. The nuclear receptor PPARbeta/delta programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes & development. 2011;25(24):2619–30. Epub 2011/12/03. doi: 10.1101/gad.178434.111 22135324; PubMed Central PMCID: PMC3248683.

28. Liang X, Liu L, Fu T, Zhou Q, Zhou D, Xiao L, et al. Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle. The Journal of biological chemistry. 2016;291(49):25306–18. Epub 2016/10/16. doi: 10.1074/jbc.M116.749424 27738103; PubMed Central PMCID: PMC5207234.

29. Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev. 2011;91(4):1447–531. Epub 2011/10/21. doi: 10.1152/physrev.00031.2010 22013216.

30. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2(5):559–69. Epub 1998/12/09. doi: 10.1016/s1097-2765(00)80155-0 9844629.

31. Park H, Tsang M, Iritani BM, Bevan MJ. Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(19):7066–71. Epub 2014/05/03. doi: 10.1073/pnas.1406473111 24785297; PubMed Central PMCID: PMC4024901.

32. Centini R, Tsang M, Iwata T, Park H, Delrow J, Margineantu D, et al. Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation. PLoS One. 2018;13(6):e0197973. Epub 2018/06/14. doi: 10.1371/journal.pone.0197973 29897930; PubMed Central PMCID: PMC5999084.

33. Yan M, Gingras MC, Dunlop EA, Nouet Y, Dupuy F, Jalali Z, et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. The Journal of clinical investigation. 2014;124(6):2640–50. Epub 2014/04/26. doi: 10.1172/JCI71749 24762438; PubMed Central PMCID: PMC4038567.

34. Possik E, Jalali Z, Nouet Y, Yan M, Gingras MC, Schmeisser K, et al. Folliculin regulates ampk-dependent autophagy and metabolic stress survival. PLoS Genet. 2014;10(4):e1004273. Epub 2014/04/26. doi: 10.1371/journal.pgen.1004273 24763318; PubMed Central PMCID: PMC3998892.

35. El-Houjeiri L, Possik E, Vijayaraghavan T, Paquette M, Martina JA, Kazan JM, et al. The Transcription Factors TFEB and TFE3 Link the FLCN-AMPK Signaling Axis to Innate Immune Response and Pathogen Resistance. Cell Rep. 2019;26(13):3613–28.e6. Epub 2019/03/28. doi: 10.1016/j.celrep.2019.02.102 30917316.

36. Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, et al. Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst. 2012;104(22):1750–64. Epub 2012/11/15. doi: 10.1093/jnci/djs418 23150719; PubMed Central PMCID: PMC3502196.

37. Bassel-Duby R, Olson EN. Signaling pathways in skeletal muscle remodeling. Annual review of biochemistry. 2006;75:19–37. Epub 2006/06/08. doi: 10.1146/annurev.biochem.75.103004.142622 16756483.

38. Potthoff MJ, Wu H, Arnold MA, Shelton JM, Backs J, McAnally J, et al. Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. The Journal of clinical investigation. 2007;117(9):2459–67. Epub 2007/09/06. doi: 10.1172/JCI31960 17786239; PubMed Central PMCID: PMC1957540.

39. van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, et al. A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Developmental cell. 2009;17(5):662–73. Epub 2009/11/20. doi: 10.1016/j.devcel.2009.10.013 19922871; PubMed Central PMCID: PMC2796371.

40. Gan Z, Rumsey J, Hazen BC, Lai L, Leone TC, Vega RB, et al. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. The Journal of clinical investigation. 2013;123(6):2564–75. Epub 2013/05/17. doi: 10.1172/JCI67652 23676496; PubMed Central PMCID: PMC3668841.

41. Yokoyama S, Ohno Y, Egawa T, Yasuhara K, Nakai A, Sugiura T, et al. Heat shock transcription factor 1-associated expression of slow myosin heavy chain in mouse soleus muscle in response to unloading with or without reloading. Acta physiologica (Oxford, England). 2016;217(4):325–37. Epub 2016/04/17. doi: 10.1111/apha.12692 27084024.

42. Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, et al. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell metabolism. 2014;20(3):526–40. Epub 2014/07/09. doi: 10.1016/j.cmet.2014.06.014 25002183.

43. Meng J, Ferguson SM. GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. The Journal of cell biology. 2018;217(8):2765–76. Epub 2018/06/01. doi: 10.1083/jcb.201712177 29848618; PubMed Central PMCID: PMC6080935.

44. Woodford MR, Dunn DM, Blanden AR, Capriotti D, Loiselle D, Prodromou C, et al. The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance drug binding. Nat Commun. 2016;7:12037. Epub 2016/06/30. doi: 10.1038/ncomms12037 27353360; PubMed Central PMCID: PMC4931344.

45. Manford AG, Rodríguez-Pérez F, Shih KY, Shi Z, Berdan CA, Choe M, et al. A Cellular Mechanism to Detect and Alleviate Reductive Stress. Cell. 2020;183(1):46–61.e21. Epub 2020/09/18. doi: 10.1016/j.cell.2020.08.034 32941802.

46. Chen Q, Xie B, Zhu S, Rong P, Sheng Y, Ducommun S, et al. A Tbc1d1 (Ser231Ala)-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice. Diabetologia. 2017;60(2):336–45. Epub 2016/11/09. doi: 10.1007/s00125-016-4151-9 27826658.

47. Fu T, Xu Z, Liu L, Guo Q, Wu H, Liang X, et al. Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity. Cell Rep. 2018;23(5):1357–72. Epub 2018/05/03. doi: 10.1016/j.celrep.2018.03.127 29719250.

48. Liu L, Cai J, Wang H, Liang X, Zhou Q, Ding C, et al. Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis. Proceedings of the National Academy of Sciences of the United States of America. 2019;116(24):11776–85. Epub 2019/05/28. doi: 10.1073/pnas.1814480116 31123148; PubMed Central PMCID: PMC6575159.

49. Liu L, Ding C, Fu T, Feng Z, Lee JE, Xiao L, et al. Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction. The Journal of clinical investigation. 2020. Epub 2020/06/17. doi: 10.1172/JCI136155 32544095.

50. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 2005;3(4):e101. Epub 2005/03/12. doi: 10.1371/journal.pbio.0030101 15760270; PubMed Central PMCID: PMC1064854.

51. Rando TA, Blau HM. Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy. The Journal of cell biology. 1994;125(6):1275–87. Epub 1994/06/01. doi: 10.1083/jcb.125.6.1275 8207057; PubMed Central PMCID: PMC2290930.

Článek vyšel v časopise

PLOS Genetics

2021 Číslo 3
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se