Altered Ca Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for Null Allele in Human Evolution

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α-Actinin-3 is a protein found inside the muscles of most people around the world. It is encoded by a gene called ACTN3, popularly known as “the gene for speed.” In 1.5 billion people, a certain variation in the genetic sequence of their ACTN3 gene causes their muscles to produce no α-actinin-3 protein at all. These people have no muscle disease; however, in elite athletes, a lack of α-actinin-3 seems to be beneficial for endurance activities and detrimental to sprinting activities. Intriguingly, α-actinin-3 deficiency varies in frequency across the globe, being most common in European and Asian populations and least common in African populations. During recent human evolution, there appears to have been strong positive selection for α-actinin-3 deficiency in places where food resources are relatively scarce and climate is cold. We have previously demonstrated that α-actinin-3 deficiency in the Actn3 knockout (KO) mouse causes a shift towards more “energy efficient” forms of muscle metabolism which would enhance survival in times of famine, and benefit endurance performance. Our present study, using single muscle fibres from Actn3 KO mice, demonstrates changes in calcium handling that would adapt muscles to cold environments and provide a survival advantage in cold climates.

Vyšlo v časopise: Altered Ca Kinetics Associated with α-Actinin-3 Deficiency May Explain Positive Selection for Null Allele in Human Evolution. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004862
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004862

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1. MacArthur DG, Seto JT, Raftery JM, Quinlan KG, Huttley GA, et al. (2007) Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat Genet 39: 1261–1265. doi: 10.1038/ng2122 17828264

2. Druzhevskaya AM, Ahmetov II, Astratenkova IV, Rogozkin VA (2008) Association of the ACTN3 R577X polymorphism with power athlete status in Russians. Eur J Appl Physiol 103: 631–634. doi: 10.1007/s00421-008-0763-1 18470530

3. Niemi AK, Majamaa K (2005) Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes. Eur J Hum Genet 13: 965–969. doi: 10.1038/sj.ejhg.5201438 15886711

4. Papadimitriou ID, Papadopoulos C, Kouvatsi A, Triantaphyllidis C (2008) The ACTN3 gene in elite Greek track and field athletes. Int J Sports Med 29: 352–355. doi: 10.1055/s-2007-965339 17879893

5. Roth SM, Walsh S, Liu D, Metter EJ, Ferrucci L, et al. (2008) The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes. Eur J Hum Genet 16: 391–394. doi: 10.1038/sj.ejhg.5201964 18043716

6. Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, et al. (2003) ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet 73: 627–631. doi: 10.1086/377590 12879365

7. Eynon N, Duarte JA, Oliveira J, Sagiv M, Yamin C, et al. (2009) ACTN3 R577X polymorphism and Israeli top-level athletes. Int J Sports Med 30: 695–698. doi: 10.1055/s-0029-1220731 19544227

8. Eynon N, Ruiz JR, Femia P, Pushkarev VP, Cieszczyk P, et al. (2012) The ACTN3 R577X polymorphism across three groups of elite male European athletes. PLoS ONE 7: e43132. doi: 10.1371/journal.pone.0043132 22916217

9. Clarkson PM, Devaney JM, Gordish-Dressman H, Thompson PD, Hubal MJ, et al. (2005) ACTN3 genotype is associated with increases in muscle strength in response to resistance training in women. J Appl Physiol 99: 154–163. doi: 10.1152/japplphysiol.01139.2004 15718405

10. Moran CN, Yang N, Bailey ME, Tsiokanos A, Jamurtas A, et al. (2007) Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks. Eur J Hum Genet 15: 88–93. doi: 10.1038/sj.ejhg.5201724 17033684

11. Vincent B, De Bock K, Ramaekers M, Van den Eede E, Van Leemputte M, et al. (2007) ACTN3 (R577X) genotype is associated with fiber type distribution. Physiol Genomics 32: 58–63. doi: 10.1152/physiolgenomics.00173.2007 17848603

12. Walsh S, Liu D, Metter EJ, Ferrucci L, Roth SM (2008) ACTN3 genotype is associated with muscle phenotypes in women across the adult age span. J Appl Physiol 105: 1486–1491. doi: 10.1152/japplphysiol.90856.2008 18756004

13. MacArthur DG, Seto JT, Chan S, Quinlan KGR, Raftery JM, et al. (2008) An Actn3 knockout mouse provides mechanistic insights into the association between α-actinin-3 deficiency and human athletic performance. Hum Mol Genet 17: 1076–1086. doi: 10.1093/hmg/ddm380 18178581

14. Quinlan KGR, Seto JT, Turner N, Vandebrouck A, Floetenmeyer M, et al. (2010) α-actinin-3 deficiency results in reduced glycogen phosphorylase activity and altered calcium handling in skeletal muscle. Hum Mol Genet 19: 1335–1346. doi: 10.1093/hmg/ddq010 20089531

15. Seto JT, Quinlan KGR, Lek M, Zheng XF, Garton F, et al. (2013) ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling. J Clin Invest 123: 4255–4263. doi: 10.1172/JCI67691 24091322

16. MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, et al. (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335: 823–828. doi: 10.1126/science.1215040 22344438

17. Friedlander SM, Herrmann AL, Lowry DP, Mepham ER, Lek M, et al. (2013) ACTN3 allele frequency in humans covaries with global latitudinal gradient. PLoS ONE 8: e52282. doi: 10.1371/journal.pone.0052282 23359641

18. Bruton JD, Aydin J, Yamada T, Shabalina IG, Ivarsson N, et al. (2010) Increased fatigue resistance linked to Ca2+-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice. J Physiol 588: 4275–4288. doi: 10.1113/jphysiol.2010.198598 20837639

19. Allen DG, Lamb GD, Westerblad H (2008) Impaired calcium release during fatigue. J Appl Physiol 104: 296–305. doi: 10.1152/japplphysiol.00908.2007 17962573

20. Allen DG, Westerblad H (1995) The effects of caffeine on intracellular calcium, force and the rate of relaxation of mouse skeletal muscle. J Physiol 487: 331–342. 8558467

21. Klein MG, Kovacs L, Simon BJ, Schneider MF (1991) Decline of myoplasmic Ca2+, recovery of calcium release and sarcoplasmic Ca2+ pump properties in frog skeletal muscle. J Physiol 441: 639–671. 1667802

22. Westerblad H, Allen DG (1994) The role of sarcoplasmic reticulum in relaxation of mouse muscle; effects of 2,5-di(tert-butyl)-1,4-benzohydroquinone. J Physiol 474: 291–301. doi: 10.1186/1471-2458-7-22 8006816

23. Allen DG, Lamb GD, Westerblad H (2008) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88: 287–332. doi: 10.1152/physrev.00015.2007 18195089

24. Trinh HH, Lamb GD (2006) Matching of sarcoplasmic reticulum and contractile properties in rat fast- and slow-twitch muscle fibres. Clin Exp Pharmacol Physiol 33: 591–600. doi: 10.1111/j.1440-1681.2006.04412.x 16789925

25. Seto JT, Chan S, Turner N, MacArthur DG, Raftery JM, et al. (2011) The effect of α-actinin-3 deficiency on muscle aging. Exp Gerontol 46: 292–302. doi: 10.1016/j.exger.2010.11.006 21112313

26. Chan S, Seto JT, Houweling PJ, Yang N, North KN, et al. (2011) Properties of extensor digitorum longus muscle and skinned fibers from adult and aged male and female Actn3 knockout mice. Muscle Nerve 43: 37–48. doi: 10.1002/mus.21778 20886650

27. Friedrich O, Weber C, von Wegner F, Chamberlain JS, Fink RH (2008) Unloaded speed of shortening in voltage-clamped intact skeletal muscle fibers from wt, mdx, and transgenic minidystrophin mice using a novel high-speed acquisition system. Biophys J 94: 4751–4765. doi: 10.1529/biophysj.107.126557 18424498

28. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91: 1447–1531. doi: 10.1152/physrev.00031.2010 22013216

29. Murphy RM, Larkins NT, Mollica JP, Beard NA, Lamb GD (2009) Calsequestrin content and SERCA determine normal and maximal Ca2+ storage levels in sarcoplasmic reticulum of fast- and slow-twitch fibres of rat. J Physiol 587: 443–460. doi: 10.1113/jphysiol.2008.163162 19029185

30. Yoshida M, Minamisawa S, Shimura M, Komazaki S, Kume H, et al. (2005) Impaired Ca2+ store functions in skeletal and cardiac muscle cells from sarcalumenin-deficient mice. J Biol Chem 280: 3500–3506. doi: 10.1074/jbc.M406618200 15569689

31. Inesi G, de Meis L (1989) Regulation of steady state filling in sarcoplasmic reticulum. Roles of back-inhibition, leakage, and slippage of the calcium pump. J Biol Chem 264: 5929–5936. 2522442

32. Lamboley CR, Murphy RM, McKenna MJ, Lamb GD (2014) Sarcoplasmic reticulum Ca2+ uptake and leak properties, and SERCA isoform expression, in type I and type II fibres of human skeletal muscle. J Physiol 592: 1381–1395. doi: 10.1113/jphysiol.2013.269373 24469076

33. Macdonald WA, Stephenson DG (2001) Effects of ADP on sarcoplasmic reticulum function in mechanically skinned skeletal muscle fibres of the rat. J Physiol 532: 499–508. doi: 10.1111/j.1469-7793.2001.0499f.x 11306667

34. Bellinger AM, Reiken S, Dura M, Murphy PW, Deng S-X, et al. (2008) Remodeling of ryanodine receptor complex causes “leaky” channels: a molecular mechanism for decreased exercise capacity. Proc Natl Acad Sci U S A 105: 2198–2202. doi: 10.1073/pnas.0711074105 18268335

35. Chen Y, Xue S, Zou J, Lopez JR, Yang JJ, et al. (2014) Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor. Biochem J 460: 261–271. doi: 10.1042/BJ20131553 24635445

36. Sjöblom B, Salmazo A, Djinović-Carugo K (2008) α-Actinin structure and regulation. Cell Mol Life Sci 65: 2688–2701. doi: 10.1007/s00018-008-8080-8 18488141

37. Lek M, North KN (2010) Are biological sensors modulated by their structural scaffolds? The role of the structural muscle proteins alpha-actinin-2 and alpha-actinin-3 as modulators of biological sensors. FEBS Lett 584: 2974–2980. doi: 10.1016/j.febslet.2010.05.059 20515688

38. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, et al. (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12: 2499–2509. doi: 10.1101/gad.12.16.2499 9716403

39. Long YC, Glund S, Garcia-Roves PM, Zierath JR (2007) Calcineurin regulates skeletal muscle metabolism via coordinated changes in gene expression. J Biol Chem 282: 1607–1614. doi: 10.1074/jbc.M609208200 17107952

40. Gailly P, Boland B, Himpens B, Casteels R, Gillis JM (1993) Critical evaluation of cytosolic calcium determination in resting muscle fibres from normal and dystrophic (mdx) mice. Cell Calcium 14: 473–483. doi: 10.1016/0143-4160(93)90006-R 8358771

41. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, et al. (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 467: 291–296. doi: 10.1038/nature09358 20693986

42. Head SI, Stephenson DG, Williams DA (1990) Properties of enzymatically isolated skeletal fibres from mice with muscular dystrophy. J Physiol 422: 351–367. 2352184

43. Calderón JC, Bolaños P, Torres SH, Rodríguez-Arroyo G, Caputo C (2009) Different fibre populations distinguished by their calcium transient characteristics in enzymatically dissociated murine flexor digitorum brevis and soleus muscles. J Muscle Res Cell Motil 30: 125–137. doi: 10.1007/s10974-009-9181-1 19543797

44. Head SI (1993) Membrane potential, resting calcium and calcium transients in isolated muscle fibres from normal and dystrophic mice. J Physiol 469: 11–19. 8271194

45. Bakker AJ, Head SI, Stephenson DG (1997) Time course of calcium transients derived from Fura-2 fluorescence measurements in single fast twitch fibres of adult mice and rat myotubes developing in primary culture. Cell Calcium 21: 359–364. doi: 10.1016/S0143-4160(97)90029-4 9174648

46. Bakker AJ, Head SI, Williams DA, Stephenson DG (1993) Ca2+ levels in myotubes grown from the skeletal muscle of dystrophic (mdx) and normal mice. J Physiol 460: 1–13. 8487190

47. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440–3450. 3838314

48. Garton F, Seto JT, North KN, Yang N (2010) Validation of an automated computational method for skeletal muscle fibre morphometry analysis. Neuromuscul Disord 20: 540–547. doi: 10.1016/j.nmd.2010.06.012 20638845