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Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 721219, 8 pages
http://dx.doi.org/10.1155/2010/721219
Review Article

The Functional Role of Calcineurin in Hypertrophy, Regeneration, and Disorders of Skeletal Muscle

1Research Center for Physical Fitness, Sports and Health, Toyohashi University of Technology, 1-1 Hibarigaoka, Tenpaku-cho, Toyohashi 441-8580, Japan
2School of Dentistry, Health Sciences University of Hokkaido, Kanazawa, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Received 30 October 2009; Accepted 9 February 2010

Academic Editor: Henk L. M. Granzier

Copyright © 2010 Kunihiro Sakuma and Akihiko Yamaguchi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. Pette and R. S. Staron, “Cellular and molecular diversities of mammalian skeletal muscle fibers,” Reviews of Physiology Biochemistry and Pharmacology, vol. 116, pp. 1–76, 1990. View at Google Scholar · View at Scopus
  2. M. W. Berchtold, H. Brinkmeier, and M. Muntener, “Calcium ion in skeletal muscle: Its crucial role for muscle function, plasticity, and disease,” Physiological Reviews, vol. 80, no. 3, pp. 1215–1265, 2000. View at Google Scholar · View at Scopus
  3. M. B. Swindells and M. Ikura, “Pre-formation of the semi-open conformation by the apo-calmodulin C-terminal domain and implications for binding IQ-motifs,” Nature Structural Biology, vol. 3, no. 6, pp. 501–504, 1996. View at Publisher · View at Google Scholar · View at Scopus
  4. R. A. Schulz and K. E. Yutzey, “Calcineurin signaling and NFAT activation in cardiovascular and skeletal muscle development,” Developmental Biology, vol. 266, no. 1, pp. 1–16, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. J. D. Molkentin, J.-R. Lu, C. L. Antos et al., “A calcineurin-dependent transcriptional pathway for cardiac hypertrophy,” Cell, vol. 93, no. 2, pp. 215–228, 1998. View at Publisher · View at Google Scholar · View at Scopus
  6. O. F. Bueno, B. J. Wilkins, K. M. Tymitz et al., “Impaired cardiac hypertrophic response in calcineurin A ß-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 7, pp. 4586–4591, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Bourajjaj, A.-S. Armand, P. A. da Costa Martins et al., “NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure,” Journal of Biological Chemistry, vol. 283, no. 32, pp. 22295–22303, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. J. Mallinson, J. Meissner, and K. C. Chang, “Chapter 2. Calcineurin signaling and the slow oxidative skeletal muscle fiber type,” International Review of Cell and Molecular Biology, vol. 277, pp. 67–101, 2009. View at Google Scholar · View at Scopus
  9. S. Schiaffino, M. Sandri, and M. Murgia, “Activity-dependent signaling pathways controlling muscle diversity and plasticity,” Physiology, vol. 22, no. 4, pp. 269–278, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Guerini and C. B. Klee, “Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 23, pp. 9183–9187, 1989. View at Publisher · View at Google Scholar · View at Scopus
  11. E. Lara-Pezzi, N. Winn, A. Paul et al., “A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration,” Journal of Cell Biology, vol. 179, no. 6, pp. 1205–1218, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. G. R. Crabtree and E. N. Olson, “NFAT signaling: choreographing the social lives of cells,” Cell, vol. 109, no. 2, supplement 1, pp. S67–S79, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. G. R. Crabtree, “Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT,” Cell, vol. 96, no. 5, pp. 611–614, 1999. View at Google Scholar · View at Scopus
  14. F. Rusnak and P. Mertz, “Calcineurin: form and function,” Physiological Reviews, vol. 80, no. 4, pp. 1483–1521, 2000. View at Google Scholar · View at Scopus
  15. R. B. Vega, B. A. Rothermel, C. J. Weinheimer et al., “Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 2, pp. 669–674, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Yang, B. Rothermel, R. B. Vega et al., “Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles,” Circulation Research, vol. 87, no. 12, pp. E61–E68, 2000. View at Google Scholar · View at Scopus
  17. N. Frey, D. Frank, S. Lippl et al., “Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation,” Journal of Clinical Investigation, vol. 118, no. 11, pp. 3598–3608, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. R. Bischoff, “The satellite cell and muscle regeneration,” in Myology, A. G. Engel and F. Armstrong, Eds., pp. 97–118, McGraw-Hill, New York, NY, USA, 1994. View at Google Scholar
  19. T. J. Hawke and D. J. Garry, “Myoegnic satellite cells: physiology to molecular biology,” Journal of Applied Physiology, vol. 91, no. 2, pp. 534–551, 2001. View at Google Scholar
  20. E. Jennische and G. L. Matejka, “IGF-I binding and IGF-I expression in regenerating muscle of normal and hypophysectomized rats,” Acta Physiologica Scandinavica, vol. 146, no. 1, pp. 79–86, 1992. View at Google Scholar · View at Scopus
  21. C. Semsarian, M.-J. Wu, Y.-K. Ju et al., “Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway,” Nature, vol. 400, no. 6744, pp. 576–581, 1999. View at Publisher · View at Google Scholar · View at Scopus
  22. G. Dobrowolny, C. Giacinti, L. Pelosi et al., “Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model,” Journal of Cell Biology, vol. 168, no. 2, pp. 193–199, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. U. Delling, J. Tureckova, H. W. Lim, L. J. De Windt, P. Rotwein, and J. D. Molkentin, “A calcineurin-NFATc3-dependent pathway regulates skeletal muscle differentiation and slow myosin heavy-chain expression,” Molecular and Cellular Biology, vol. 20, no. 17, pp. 6600–6611, 2000. View at Publisher · View at Google Scholar · View at Scopus
  24. B. B. Friday, V. Horsley, and G. K. Pavlath, “Calcineurin activity is required for the initiation of skeletal muscle differentiation,” Journal of Cell Biology, vol. 149, no. 3, pp. 657–666, 2000. View at Publisher · View at Google Scholar · View at Scopus
  25. B. B. Friday, P. O. Mitchell, K. M. Kegley, and G. K. Pavlath, “Calcineurin initiates skeletal muscle differentiation by activating MEF2 and MyoD,” Differentiation, vol. 71, no. 3, pp. 217–227, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Sakuma, J. Nishikawa, R. Nakao et al., “Calcineurin is a potent regulator for skeletal muscle regeneration by association with NFATc1 and GATA-2,” Acta Neuropathologica, vol. 105, no. 3, pp. 271–280, 2003. View at Google Scholar · View at Scopus
  27. K. L. Abbott, B. B. Friday, D. Thaloor, T. J. Murphy, and G. K. Pavlath, “Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells,” Molecular Biology of the Cell, vol. 9, no. 10, pp. 2905–2916, 1998. View at Google Scholar · View at Scopus
  28. N. Koulmann, H. Sanchez, B. N'Guessan et al., “The responsiveness of regenerated soleus muscle to pharmacological calcineurin inhibition,” Journal of Cellular Physiology, vol. 208, no. 1, pp. 116–122, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. N. Stupka, J. D. Schertzer, R. Bassel-Duby, E. N. Olson, and G. S. Lynch, “Calcineurin-Aα activation enhances the structure and function of regenerating muscles after myotoxic injury,” American Journal of Physiology, vol. 293, no. 2, pp. R686–R694, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Grobet, D. Pirottin, F. Farnir et al., “Modulating skeletal muscle mass by postnatal, muscle-specific inactivation of the myostatin gene,” Genesis, vol. 35, no. 4, pp. 227–238, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. A. C. McPherron, A. M. Lawler, and S.-J. Lee, “Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member,” Nature, vol. 387, no. 6628, pp. 83–90, 1997. View at Google Scholar · View at Scopus
  32. K. Sakuma, R. Nakao, W. Aoi et al., “Cyclosporin A treatment upregulates Id1 and Smad3 expression and delays skeletal muscle regeneration,” Acta Neuropathologica, vol. 110, no. 3, pp. 269–280, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. N. Al-Shanti and C. E. Stewart, “Ca2+/calmodulin-dependent transcriptional pathways: potential mediators of skeletal muscle growth and development,” Biological Reviews, vol. 84, no. 4, pp. 637–652, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. R. N. Michel, S. E. Dunn, and E. R. Chin, “Calcineurin and skeletal muscle growth,” Proceedings of the Nutrition Society, vol. 63, no. 2, pp. 341–349, 2004. View at Publisher · View at Google Scholar · View at Scopus
  35. R. N. Michel, E. R. Chin, J. V. Chakkalakal, J. K. Eibl, and B. J. Jasmin, “Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression,” Applied Physiology, Nutrition and Metabolism, vol. 32, no. 5, pp. 921–929, 2007. View at Publisher · View at Google Scholar · View at Scopus
  36. K. Sakuma, K. Watanabe, M. Sano, I. Uramoto, and T. Totsuka, “Differential adaptation of growth and differentiation factor 8/myostatin, fibroblast growth factor 6 and leukemia inhibitory factor in overloaded, regenerating and denervated rat muscles,” Biochimica et Biophysica Acta, vol. 1497, no. 1, pp. 77–88, 2000. View at Publisher · View at Google Scholar · View at Scopus
  37. K. Sakuma, K. Watanabe, N. Hotta et al., “The adaptive responses in several mediators linked with hypertrophy and atrophy of skeletal muscle after lower limb unloading in humans,” Acta Physiologica, vol. 197, no. 2, pp. 151–159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. M. Wehling, B. Cai, and J. G. Tidball, “Modulation of myostatin expression during modified muscle use,” FASEB Journal, vol. 14, no. 1, pp. 103–110, 2000. View at Google Scholar · View at Scopus
  39. N. F. Gonzalez-Cadavid, W. E. Taylor, K. Yarasheski et al., “Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 25, pp. 14938–14943, 1998. View at Google Scholar
  40. D. L. Allen and T. G. Unterman, “Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors,” American Journal of Physiology, vol. 292, no. 1, pp. C188–C199, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Langley, M. Thomas, A. Bishop, M. Sharma, S. Gilmour, and R. Kambadur, “Myostatin inhibits myoblast differentiation by down-regulating MyoD expression,” Journal of Biological Chemistry, vol. 277, no. 51, pp. 49831–49840, 2002. View at Publisher · View at Google Scholar · View at Scopus
  42. S. K. Muthuri, E. R. Chin, and R. N. Michel, “Myostatin as a putative downstream gene target of calcineurin signaling associated with muscle growth remodeling,” FASEB Journal, vol. 21, p. 895.14, 2007. View at Google Scholar
  43. H.-H. Li, V. Kedar, C. Zhang et al., “Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex,” Journal of Clinical Investigation, vol. 114, no. 8, pp. 1058–1071, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. G. Ni, K. Berenji, N. Wang et al., “Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling,” Circulation, vol. 114, no. 11, pp. 1159–1168, 2006. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Sandri, C. Sandri, A. Gilbert et al., “Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy,” Cell, vol. 117, no. 3, pp. 399–412, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. T. N. Stitt, D. Drujan, B. A. Clarke et al., “The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors,” Molecular Cell, vol. 14, no. 3, pp. 395–403, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. R. A. Frost and C. H. Lang, “Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass,” Journal of Applied Physiology, vol. 103, no. 1, pp. 378–387, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. D. J. Glass, “Skeletal muscle hypertrophy and atrophy signaling pathways,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 10, pp. 1974–1984, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. C. Rommel, S. C. Bodine, B. A. Clarke et al., “Mediation of IGF-1-induced skeletal myotube hypertrophy by Pl(3)K/Akt/mTOR and Pl(3)K/Akt/GSK3 pathways,” Nature Cell Biology, vol. 3, no. 11, pp. 1009–1013, 2001. View at Publisher · View at Google Scholar · View at Scopus
  50. A. Musaró, K. J. A. McCullagh, F. J. Naya, E. N. Olson, and N. Rosenthal, “IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1,” Nature, vol. 400, no. 6744, pp. 581–585, 1999. View at Publisher · View at Google Scholar · View at Scopus
  51. S. E. Dunn, J. L. Burns, and R. N. Michel, “Calcineurin is required for skeletal muscle hypertrophy,” Journal of Biological Chemistry, vol. 274, no. 31, pp. 21908–21912, 1999. View at Publisher · View at Google Scholar · View at Scopus
  52. F. J. Naya, B. Mercer, J. Shelton, J. A. Richardson, R. S. Williams, and E. N. Olson, “Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo,” Journal of Biological Chemistry, vol. 275, no. 7, pp. 4545–4548, 2000. View at Publisher · View at Google Scholar · View at Scopus
  53. S. C. Bodine, T. N. Stitt, M. Gonzalez et al., “Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo,” Nature Cell Biology, vol. 3, no. 11, pp. 1014–1019, 2001. View at Publisher · View at Google Scholar · View at Scopus
  54. S. A. Parsons, B. J. Wilkins, O. F. Bueno, and J. D. Molkentin, “Altered skeletal muscle phenotypes in calcineurin Aα and Aβ gene-targeted mice,” Molecular and Cellular Biology, vol. 23, no. 12, pp. 4331–4343, 2003. View at Publisher · View at Google Scholar · View at Scopus
  55. S. A. Parsons, D. P. Millay, B. J. Wilkins et al., “Genetic loss of calcineurin blocks mechanical overload-induced skeletal muscle fiber type switching but not hypertrophy,” Journal of Biological Chemistry, vol. 279, no. 25, pp. 26192–26200, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. R. J. Talmadge, J. S. Otis, M. R. Rittler et al., “Calcineurin activation influences muscle phenotype in a muscle-specific fashion,” BMC Cell Biology, vol. 5, article 28, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. K.-M. V. Lai, M. Gonzalez, W. T. Poueymirou et al., “Conditional activation of Akt in adult skeletal muscle induces rapid hypertrophy,” Molecular and Cellular Biology, vol. 24, no. 21, pp. 9295–9304, 2004. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Oh, I. I. Rybkin, V. Copeland et al., “Calcineurin is necessary for the maintenance but not embryonic development of slow muscle fibers,” Molecular and Cellular Biology, vol. 25, no. 15, pp. 6629–6638, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Sakuma, M. Akiho, H. Nakashima et al., “Cyclosporin A modulates cellular localization of MEF2C protein and blocks fiber hypertrophy in the overloaded soleus muscle of mice,” Acta Neuropathologica, vol. 115, no. 6, pp. 663–674, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. P. O. Mitchell, S. T. Mills, and G. K. Pavlath, “Calcineurin differentially regulates maintenance and growth of phenotypically distinct muscles,” American Journal of Physiology, vol. 282, no. 5, pp. C984–C992, 2002. View at Google Scholar · View at Scopus
  61. M. Miyazaki, Y. Hitomi, T. Kizaki et al., “Calcineurin-mediated slow-type fiber expression and growth in reloading condition,” Medicine and Science in Sports and Exercise, vol. 38, no. 6, pp. 1065–1072, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. Y. Oishi, T. Ogata, K.-I. Yamamoto et al., “Cellular adaptations in soleus muscle during recovery after hindlimb unloading,” Acta Physiologica, vol. 192, no. 3, pp. 381–395, 2008. View at Publisher · View at Google Scholar · View at Scopus
  63. J. D. Molkentin, J.-R. Lu, C. L. Antos et al., “A calcineurin-dependent transcriptional pathway for cardiac hypertrophy,” Cell, vol. 93, no. 2, pp. 215–228, 1998. View at Publisher · View at Google Scholar · View at Scopus
  64. B. J. Wilkins and J. D. Molkentin, “Calcineurin and cardiac hypertrophy: where have we been? Where are we going?” The Journal of Physiology, vol. 541, no. 1, pp. 1–8, 2002. View at Google Scholar
  65. S. E. Dunn, E. R. Chin, and R. N. Michel, “Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth,” Journal of Cell Biology, vol. 151, no. 3, pp. 663–672, 2000. View at Publisher · View at Google Scholar · View at Scopus
  66. V. Horsley, B. B. Friday, S. Matteson, K. M. Kegley, J. Gephart, and G. K. Pavlath, “Regulation of the growth of multinucleated muscle cells by an NFATC2-dependent pathway,” Journal of Cell Biology, vol. 153, no. 2, pp. 329–338, 2001. View at Publisher · View at Google Scholar · View at Scopus
  67. K. M. Kegley, J. Gephart, G. L. Warren, and G. K. Pavlath, “Altered primary myogenesis in NFATC3-/- mice leads to decreased muscle size in the adult,” Developmental Biology, vol. 232, no. 1, pp. 115–126, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. Y. Hinits and S. M. Hughes, “Mef2s are required for thick filament formation in nascent muscle fibres,” Development, vol. 134, no. 13, pp. 2511–2519, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. M. J. Potthoff, M. A. Arnold, J. McAnally, J. A. Richardson, R. Bassel-Duby, and E. N. Olson, “Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by Mef2c,” Molecular and Cellular Biology, vol. 27, no. 23, pp. 8143–8151, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. S. E. Dunn, A. R. Simard, R. Bassel-Duby, R. S. Williams, and R. N. Michel, “Nerve activity-dependent modulation of calcineurin signaling in adult fast and slow skeletal muscle fibers,” Journal of Biological Chemistry, vol. 276, no. 48, pp. 45243–45254, 2001. View at Publisher · View at Google Scholar · View at Scopus
  71. C. M. Alfieri, H. J. Evans-Anderson, and K. E. Yutzey, “Developmental regulation of the mouse IGF-I exon 1 promoter region by calcineurin activation of NFAT in skeletal muscle,” American Journal of Physiology, vol. 292, no. 5, pp. C1887–C1894, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. D. L. Allen, J. J. Uyenishi, A. S. Cleary, R. S. Mehan, S. F. Lindsay, and J. M. Reed, “Calcineurin activates interleukin-6 transcription in mouse skeletal muscle in vivo and in C2C12 myotubes in vitro,” American Journal of Physiology, vol. 298, no. 1, pp. R198–R210, 2010. View at Publisher · View at Google Scholar · View at Scopus
  73. A. C. Paul and N. Rosenthal, “Different modes of hypertrophy in skeletal muscle fibers,” Journal of Cell Biology, vol. 156, no. 4, pp. 751–760, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. J. V. Chakkalakal, M. A. Stocksley, M.-A. Harrison et al., “Expression of utrophin A mRNA correlates with the oxidative capacity of skeletal muscle fiber types and is regulated by calcineurin/NFAT signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 13, pp. 7791–7796, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. J. V. Chakkalakal, M.-A. Harrison, S. Carbonetto, E. Chin, R. N. Michel, and B. J. Jasmin, “Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice,” Human Molecular Genetics, vol. 13, no. 4, pp. 379–388, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Stupka, P. Gregorevic, D. R. Plant, and G. S. Lynch, “The calcineurin signal transduction pathway is essential for successful muscle regeneration in mdx dystrophic mice,” Acta Neuropathologica, vol. 107, no. 4, pp. 299–310, 2004. View at Publisher · View at Google Scholar · View at Scopus
  77. L. M. Angus, J. V. Chakkalakal, A. Mejat et al., “Calcineurin-NFAT signaling, together with GABP and PGC-1a, drives utrophin gene expression at the neuromuscular junction,” American Journal of Physiology, vol. 289, no. 4, pp. C908–C917, 2005. View at Google Scholar
  78. J. V. Chakkalakal, S. A. Michel, E. R. Chin, R. N. Michel, and B. J. Jasmin, “Targeted inhibition of Ca2+/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle,” Human Molecular Genetics, vol. 15, no. 9, pp. 1423–1435, 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. N. Stupka, B. J. Michell, B. E. Kemp, and G. S. Lynch, “Differential calcineurin signalling activity and regeneration efficacy in diaphragm and limb muscles of dystrophic mdx mice,” Neuromuscular Disorders, vol. 16, no. 5, pp. 337–346, 2006. View at Publisher · View at Google Scholar · View at Scopus
  80. N. Stupka, D. R. Plant, J. D. Schertzer et al., “Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice,” Journal of Physiology, vol. 575, no. 2, pp. 645–656, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. A. Angelin, T. Tiepolo, P. Sabatelli et al., “Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 3, pp. 991–996, 2007. View at Publisher · View at Google Scholar · View at Scopus
  82. S. A. Parsons, D. P. Millay, M. A. Sargent et al., “Genetic disruption of calcineurin improves skeletal muscle pathology and cardiac disease in a mouse model of limb-girdle muscular dystrophy,” Journal of Biological Chemistry, vol. 282, no. 13, pp. 10068–10078, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. N. Stupka, J. D. Schertzer, R. Bassel-Duby, E. N. Olson, and G. S. Lynch, “Stimulation of calcineurin Aalpha activity attenuates muscle pathophysiology in mdx dystrophic mice,” American Journal of Physiology, vol. 294, no. 3, pp. R983–R992, 2008. View at Google Scholar
  84. L. Merlini, A. Angelin, T. Tiepolo et al., “Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 13, pp. 5225–5229, 2008. View at Publisher · View at Google Scholar · View at Scopus