Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Calcineurin differentially regulates fast myosin heavy chain genes in oxidative muscle fibre type conversion

Abstract

In skeletal muscle, calcineurin is crucial for myocyte differentiation and in the determination of the slow oxidative fibre phenotype, both processes being important determinants of muscle performance, metabolic health and meat-animal production. Fibre type is defined by the isoform identity of the skeletal myosin heavy chain (MyHC). We have examined the responses of the major MyHC genes to calcineurin signalling during fibre formation of muscle C2C12 cells. We have found that calcineurin acts as a signal to up-regulate the fast-oxidative MyHC2a gene and to down-regulate the faster MyHC2x and MyHC2b genes in a manner that appears to be NFAT-independent. Contrary to expectation, the up-regulation of MyHCslow by calcineurin seems to be time-dependent and is only detectable once the initial differential expression of the post-natal fast MyHC genes has been established. The simultaneous elevated expression of MyHC2a and the repression of MyHC2x and MyHC2b expression indicate that both processes (elevation and repression) are actively coordinated during oxidative fibre conversion. We have further determined that muscle LIM protein (MLP), a calcineurin-binding Z-line co-factor, is induced by calcineurin and that its co-expression with calcineurin has an additive effect on MyHCslow expression. Hence, post-natal fast MyHCs are important early effector targets of calcineurin, whereas MyHCslow up-regulation is mediated in part by calcineurin-induced MLP.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 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. J Biol Chem 277:45323–45330

  2. Allen DL, Sartorius CA, Sycuro LK, Leinwand LA (2001) Different pathways regulate expression of the skeletal myosin heavy chain genes. J Biol Chem 276:43524–43533

  3. Alzuherri H, Chang KC (2003) Calcineurin activates NF-κB in skeletal muscle C2C12 cells. Cell Signal 15:471–478

  4. Aramburu J, Yaffe MB, López-Rodriguez C, Cantley LC, Hogan PG, Rao A (1999) Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285:2129–2133

  5. Arber S, Halder G, Caroni P (1994) Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell 79:221–231

  6. Bai Q, McGillivray C, Costa N da, Dornan S, Evans G, Stear MJ, Chang KC (2003) Development of a porcine skeletal muscle cDNA microarray: analysis of differential transcript expression in phenotypically distinct muscles. BMC Genomics 4:8

  7. Barash IA, Mathew L, Lahey M, Greaser ML, Lieber RL (2005) Muscle LIM protein plays both structural and functional roles in skeletal muscle. Am J Physiol Cell Physiol 289:C1312–C1320

  8. Bassel-Duby R, Olson EN (2003) Role of calcineurin in striated muscle: development, adaptation, and disease. Biochem Biophy Res Commun 311:1133–1141

  9. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12:2499–2509

  10. Costa N da, Blackley R, Alzuherri H, Chang KC (2002) Quantifying the temporo-spatial expression of porcine postnatal skeletal myosin heavy chain genes. J Histochem Cytochem 50:353–364

  11. Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P, Molkentin JD (2000) A calcineurin-NFATc3-dependent pathway regulates skeletal muscle differentiation and slow myosin heavy-chain expression. Mol Cell Biol 20:6600–6611

  12. Edgar JM, Price DJ (2001) Radial migration in the cerebral corte is enhanced by signals from thalamus. Eur J Neurosci 13:1745–1754

  13. Friday BB, Horsley V, Pavlath GK (2000) Calcineurin activity is required for the initiation of skeletal muscle differentiation. J Cell Biol 149:657–665

  14. Friday BB, Mitchell PO, Kegley KM, Pavlath GK (2003) Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD. Differentiation 71:217–227

  15. Glass DJ (2005) Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 37:1974–1984

  16. Hong F, Lee J, Song JW, Lee SJ, Ahn H, Cho JJ, Ha J, Kim SS (2002) Cyclosporin blocks muscle differentiation by inducing oxidative stress and by inhibiting the peptidylprolyl-cis-trans-isomerase activity of cyclophilin A: cyclophilin A protects myoblasts from cyclosporine-induced cytotoxicity. FASEB J 16:1633–1635

  17. Horsley V, Friday BB, Matteson S, Kegley KM, Gephart J, Pavlath GK (2001) Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway. J Cell Biol 153:329–338

  18. Im SH, Rao A (2004) Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Mol Cells 18:1–9

  19. Kegley KM, Gephart J, Warren GL, Pavlath GK (2001) Altered primary myogenesis in NFATC3-/- mice leads to decreased muscle size in the adult. Dev Biol 232:115–126

  20. Kong Y, Flick MJ, Kudla AJ, Konieczny SF (1997) Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD. Mol Cell Biol 17:4750–4760

  21. Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G (2003) Ca2+ transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture. Am J Physiol Cell Physiol 285:C56–C63

  22. Liu Y, Shen T, Randall WR, Schneider MF (2005) Signaling pathways in activity-dependent fiber type plasticity in adult skeletal muscle. J Muscle Res Cell Motil 26:13–21

  23. Lu PY, Taylor M, Jia HT, Ni JH (2004) Muscle LIM protein promotes expression of the acetylcholine receptor g-subunit gene cooperatively with the myogenin-E12 complex. Cell Mol Life Sci 61:2386–2392

  24. McCullagh KJA, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL, Argentini C, Kalhovde JM, Lomo T, Schiaffino S (2004) NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching. Proc Natl Acad Sci USA 101:10590–10595

  25. Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson EN (2000) Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo. J Biol Chem 275:4545–4548

  26. Oh M, Rybkin II, Copeland V, Czubryt MP, Shelton JM, Rooij E van, Richardson JA, Hill JA, De Windt LJ, Bassel-Duby R, Olson EN, Rothermel BA (2005) Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers. Mol Cell Biol 25:6629–6638

  27. Parsons SA, Wilkins BJ, Bueno OF, Molkentin JD (2003) Altered skeletal muscle phenotypes in calcineurin Aa and Ab gene-targeted mice. Mol Cell Biol 23:4331–4343

  28. Parsons SA, Millay DP, Wilkins BJ, Bueno OF, Tsika GL, Neilson JR, Liberatore CM, Yutzey KE, Crabtree GR, Tsika RW, Molkentin JD (2004) Genetic loss of calcineurin blocks mechanical over-load induced skeletal fiber type switching but not hypertrophy. J Biol Chem 279:26192–26200

  29. Pette D, Staron RS (2000) Myosins isoforms, muscle fiber types, and transitions. Microsc Res Tech 50:500–509

  30. Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747

  31. Rothermel BA, McKinsey TA, Vega RB, Nicol RL, Mammen P, Yang J, Antos CL, Shelton JM, Bassel-Duby R, Olson EN, Williams RS (2001) Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. Proc Natl Acad Sci USA 98:3328–3333

  32. Sanna B, Brandt EB, Kaiser RA, Pfluger P, Witt SA, Kimball TR, Rooij E van, De Windt LJ, Rothenberg ME, Tschop MH, Benoit SC, Molkentin JD (2006) Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo. Proc Natl Acad Sci USA 103:7327–7332

  33. Schneider AG, Sultan KR, Pette D (1999) Muscle LIM protein: expressed in slow muscle and induced in fast muscle by enhanced contractile activity. Am J Physiol Cell Physiol 276:C900–C906

  34. Schulz RA, Yutzey KE (2004) Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development. Dev Biol 266:1–16

  35. Serrano AL, Murgia M, Pallafacchina G, Calabria E, Coniglio P, Schiaffino S (2001) Calcineurin controls nerve activity-dependent specification of slow skeletal muscle fibers but not muscle growth. Proc Natl Acad Sci USA 98:13108–13113

  36. Siddiq A, Miyazaki T, Takagishi Y, Kanou Y, Hayasaka S, Inouye M, Seo H, Murata Y (2001) Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism. Endocrinology 142:1752–1759

  37. Sugiura T, Abe N, Nagano M, Goto K, Sakuma K, Naito H, Yoshioka T, Powers SK (2005) Changes in PKB/Akt and calcineurin signaling during recovery in atrophied soleus muscle induced by unloading. Am J Physiol Regul Integr Comp Physiol 288:R1273–R1278

  38. Sun YM, Costa N da, Chang KC (2003) Cluster characterisation and temporal expression of porcine sarcomeric myosin heavy chain genes. J Muscle Res Cell Motil 24:561–570

  39. Swoap SJ, Hunter RB, Stevenson EJ, Felton HM, Kansagra NV, Lang JM, Esser KA, Kandarian SC (2000) The calcineurin-NFAT pathway and muscle fiber-type gene expression. Am J Physiol Cell Physiol 279:C915–C924

  40. Talmadge RJ, Otis JS, Rittler MR, Garcia ND, Spencer SR, Lees SJ, Naya FJ (2004) Calcineurin activation influences muscle phenotype in a muscle-specific fashion. BMC Cell Biol 5:28

  41. Torgan CE, Daniels MP (2001) Regulation of myosin heavy chain expression during rat skeletal muscle development in vitro. Mol Biol Cell 12:1499–1508

  42. Vega RB, Rothermel BA, Weinheimer CJ, Kovacs A, Naseem RH, Bassel-Duby R, Williams RS, Olson EN (2003) Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy. Proc Natl Acad Sci USA 100:669–674

  43. Weiss A, McDonough D, Wertman B, Acakpo-Satchivi L, Montgomery K, Kucherlapati R, Leinwand L, Krauter K (1999a) Organisation of human and mouse skeletal myosin heavy chain gene clusters is highly conserved. Proc Natl Acad Sci USA 96:2958–2963

  44. Weiss A, Schiaffino S, Leinwand LA (1999b) Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity. J Mol Biol 290:61–75

  45. Wu H, Naya FJ, McKinsey TA, Mercer B, Shelton JM, Chin ER, Simard AR, Michel RN, Bassel-Duby R, Olson EN, Williams RS (2000) MEF2 responds to multiple calcium-regulated signals in the control of skeletal muscle fiber type. EMBO J 19:1963–1973

  46. Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, Williams RS (2001) Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO J 20:6414–6423

  47. Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, Williams RS (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352

  48. Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS (2000) Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res 87:61–68

Download references

Author information

Correspondence to Kin-Chow Chang.

Additional information

This work was supported by the Biotechnology and Biological Sciences Research Council and was carried out in collaboration with the company Genus.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

da Costa, N., Edgar, J., Ooi, P. et al. Calcineurin differentially regulates fast myosin heavy chain genes in oxidative muscle fibre type conversion. Cell Tissue Res 329, 515–527 (2007). https://doi.org/10.1007/s00441-007-0441-3

Download citation

Keywords

  • Calcineurin
  • Myosin heavy chain
  • Fibre type
  • Oxidative
  • Muscle LIM protein
  • C2C12 cells