Molecular and Cellular Biochemistry

, Volume 179, Issue 1–2, pp 135–145 | Cite as

Exercise-induced muscle injury: A calpain hypothesis

  • Angelo N. Belcastro
  • Leann D. Shewchuk
  • Daniel A. Raj

Abstract

It is well established that periods of increased contractile activity result in significant changes in muscle structure and function. Such morphological changes as sarcomeric Z-line disruption and sarcoplasmic reticulum vacuolization are characteristic of exercise-induced muscle injury. While the precise mechanism(s) underlying the perturbations to muscle following exercise remains to be elucidated, it is clear that disturbances in Ca2+ homeostasis and changes in the rate of protein degradation occur. The resulting elevation in intracellular [Ca2+] activates the non-lysosomal cysteine protease, calpain. Because calpain cleaves a variety of protein substrates including cytoskeletal and myofibrillar proteins, calpain-mediated degradation is thought to contribute to the changes in muscle structure and function that occur immediately following exercise. In addition, calpain activation may trigger the adaptation response to muscle injury. The purpose of this paper is to: (i) review the chemistry of the calpain-calpastatin system; (ii) provide evidence for the involvement of the non-lysosomal, calcium-activated neutral protease (calpain) in the response of skeletal muscle protein breakdown to exercise (calpain hypothesis); and (iii) describe the possible involvement of calpain in the inflammatory and regeneration response to exercise.

calcium non-lysosomal proteases muscle damage neutrophils muscle regeneration 

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References

  1. 1.
    Rennie MJ, Edwards HT, Krywawych S, Davies CTM, Halliday D, Waterlow JC, Millward DJ: Effect of exercise on protein turnover in man. Clin Sci 61: 627–639, 1981Google Scholar
  2. 2.
    Kasperek GJ, Snider RD: Total and myofibrillar protein degradation in isolated soleus muscles after exercise. Am J Physiol 257: E1–E5, 1989Google Scholar
  3. 3.
    Dohm GL, Williams RT, Kasperek GJ, Askew EW: Biphasic changes in 3-methylhistidine excretion in humans after exercise. J Appl Physiol 52: 27–33, 1982Google Scholar
  4. 4.
    Davies CT, Halliday D, Millward D, Rennie MJ, Sutton JR: Glucose inhibits CO2 production from leucine during whole-body exercise in man. J Physiol 332: 40–41, 1982Google Scholar
  5. 5.
    Graham TE, MacLean DA: Ammonia and amino acid metabolism in human skeletal muscle during exercise. Can J Physiol Pharmacol 70: 132–141, 1992Google Scholar
  6. 6.
    Graham TE, Kiens B, Hargarves M, Richter EA: Influence of fatty acids on ammonia and amino acid flux from active human muscle. Am J Physiol 261: E168–E176, 1991Google Scholar
  7. 7.
    Dohm GL, Kasperek GJ, Tapscott EB, Beecher GR: Effect of exercise on synthesis and degradation of muscle protein. Biochem J 188: 255–262, 1980Google Scholar
  8. 8.
    Davis TA, Karl IE: Response of muscle protein turnover to insulin after acute exercise and training. Biochem J 240: 651–657, 1986Google Scholar
  9. 9.
    Tapscott EB, Kasperek GJ, Dohm GL: Effect of training on muscle protein turnover in male and female rats. Biochem Med 27: 254–259, 1982Google Scholar
  10. 10.
    Salminen A, Vihko V: Effects of age and prolonged running on proteolytic capacity in mouse cardiac and skeletal muscles. Acta Physiol Scand 112: 89–95, 1981Google Scholar
  11. 11.
    Vihko V, Rantamaki J, Salminen A: Exhaustive physical exercise and acid hydrolase activity in mouse skeletal muscle: A histochemical study. Histochem 57: 237–249, 1978Google Scholar
  12. 12.
    Salminen A, Vihko V: Autophagic response to strenuous exercise in mouse skeletal muscle fibers. Virchow Arch 45: 97–106, 1984Google Scholar
  13. 13.
    Belcastro AN, MacLean I, Gilchrist J: Biochemical basis of muscular fatigue associated with repetitous contractions of skeletal muscle. Int J Biochem 17: 447–453, 1985Google Scholar
  14. 14.
    Brooks BA, Goll DE, Peng YS, Grewling JA, Hennecke G: Effect of starvation and refeeding on activity of Ca2+-dependent protease in rat skeletal muscle. J Nutr 113: 145–158, 1983Google Scholar
  15. 15.
    Dayton WR, Goll DE, Stromer MH, Reville WJ, Zeece MG: Some properties of a Ca2+-activated protease that may be involved in myofibrillar protein turnover. In: E Reich, DB Rifkin, E Shaw (eds). Proteases and Biological Control. Cold Spring Harbor Lab., New York, 1975, pp 551–557Google Scholar
  16. 16.
    Smith LL: Acute inflammation: the underlying mechanism in delayed onset muscle soreness? Med Sci Sports Exerc 23: 542–551, 1991Google Scholar
  17. 17.
    Van der Westhuyzen DR, Matsumoto K, Etlinger JD: Easily releasable myofilaments from skeletal and cardiac muscles maintained in vivo. J Biol Chem 256: 11791–11797, 1981Google Scholar
  18. 18.
    Zeman RJ, Kameyama T, Matsumoto K, Bernstein P, Etlinger JD: Regulation of protein degradation in muscle by calcium. J Biol Chem 260: 13619–13624, 1985Google Scholar
  19. 19.
    Tidball JG: Inflammatory cell response to acute muscle injury. Med Sci Sports Exerc 27: 1022–1032, 1995Google Scholar
  20. 20.
    Cannon JG, Meydani SN, Fielding RA, Fiatarone MA, Meydani M, Farhangmehr M, Orencole SF, Blumberg JB, Evans WJ: Acute phase response in exercise II. Associations between vitamin E, cytokines, and muscle proteolysis. Am J Physiol 260: R1235–R1240, 1991Google Scholar
  21. 21.
    Armstrong RB, Ogilvie RW, Schwane JA: Eccentric exercise-induced injury to rat skeletal muscle. J Appl Physiol 54: 80–93, 1983Google Scholar
  22. 22.
    Fridén J, Sfakianos PN, Hargens AR: Blood indices of muscle injury associated with eccentric muscle contractions. J Orthopaedic Res 7: 142–145, 1989Google Scholar
  23. 23.
    Belcastro AN, Parkhouse W, Dobson G, Gilchrist JS: Influence of exercise on cardiac and skeletal muscle myofibrillar proteins. Mol Cell Biochem 83: 27–36, 1988Google Scholar
  24. 24.
    Clarkson PM, Tremblay I: Exercise-induced muscle damage, repair, and adaptation in humans. J Appl Physiol 65: 1–6, 1988Google Scholar
  25. 25.
    Sorimachi H, Ohmi S, Emori Y, Kawasaki H, Saido TC, Ohno S, Minami Y, Suzuki K: A novel member of the calcium-dependent cysteine protease family. Biol Chem Hoppe-Seyler 371: 171–176, 1990Google Scholar
  26. 26.
    Sorimachi H, Imajoh S, Emori Y, Kawasaki H, Ohno S, Minami Y, Suzuki K: Molecular cloning of a novel mammalian calcium-dependent protease distinct from both µ-and m-types: specific expression of the mRNA in skeletal muscle. J Biol Chem 264: 20106–20111, 1989Google Scholar
  27. 27.
    Sorimachi H, Toyama-Sorimachi N, Saido TC, Kawasaki H, Sugita H, Miyasaka M, Arahata K, Ishiura S, Suzuki K: Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle. J Biol Chem 268: 10593–10605, 1993Google Scholar
  28. 28.
    Sorimachi H, Saido TC, Suzuki K: New era of calpain research. FEBS Lett 343: 1–5, 1994Google Scholar
  29. 29.
    Gregoriou AC, Pearson MA, Crawford C: The calpain cleavage sites in the epidermal growth factor kinase domain. Eur J Biochem 223: 455–464, 1994Google Scholar
  30. 30.
    Viru A: Postexercise recovery period: carbohydrate and protein metabolism. Scand J Med Sci Sports 6: 2–14, 1996Google Scholar
  31. 31.
    Goll DE, Thompson VF, Taylor RG, Zalewska T: Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin. BioEssays 14.J: 549–56, 1992Google Scholar
  32. 32.
    Kawasaki H, Emori Y, Imajoh-Ohmi S, Minami Y, Suzuki K: Identification and characterization of inhibitory sequences in four repeating domains of the endogenous inhibitor for calcium-dependent protease. J Biochem 106: 274–281, 1989Google Scholar
  33. 33.
    Kumamoto T, Kleese WC, Cong J, Goll DE, Pierce PR, Allen RE: Localization of the Ca2+-dependent proteinase and their inhibitor in normal, fasted, denervated rat skeletal muscle. Anat Rec 232: 60–77, 1992Google Scholar
  34. 34.
    Kapprell HP, Goll DE: Effect of Ca2+ on binding of calpains to calpastatin. J Biol Chem 264: 17888–17896, 1989Google Scholar
  35. 35.
    Adachi Y, Ishida-Takahashi A, Takahashi C, Takano E, Murachi T, Hatanaka M: Phosphorylation and subcellular distribution of calpastatin in human hematopoietic system cells. J Biol Chem 266: 3968–3972, 1991Google Scholar
  36. 36.
    Inomata M, Hayashi M, Nakamura M, Saito Y, Kawashima S: Properties of erythrocyte membrane binding and autolytic activation of calcium activated neutral protease. J Biol Chem 264: 18838–18843, 1989Google Scholar
  37. 37.
    Kuboki M, Ishii H, Kazama M: Characterization of calpain I-binding proteins in humans erythrocyte plasma membrane. J Biochem 107: 776–780, 1990Google Scholar
  38. 38.
    Saido TC, Sorimachi H, Suzuki K: Calpain: new perspective in molecular diversity and physiological-pathological involvement. FASEB J 8814–8822, 1994Google Scholar
  39. 39.
    Yoshizawa T, Sorimachi H, Tomioka S, Ishiura S, Suzuki K: Calpain dissociates into subunits in the presence of calcium ions. Biochem Biophys Res Comm 208: 376–383, 1995Google Scholar
  40. 40.
    Johnson P: Calpain: structure-activity relationship and involvement in normal and abnormal cellular metabolism. Int J Biochem 263: 823–828, 1990Google Scholar
  41. 41.
    Suzuki K, Ohno S: Calcium activated neutral protease: structurefunction relationship and functional implications. Cell Struct Funct 15: 1–6, 1990Google Scholar
  42. 42.
    Belcastro AN, Gilchrist JS, Scrubb JA, Arthur G: Calcium-supported calpain degradation rates for cardiac myofibrils in diabetes: sulfhydryl and hydrophobic interactions. Mol Cell Biochem 135: 51–60, 1994Google Scholar
  43. 43.
    Bond JS, Butler PE: Intracellular proteases. Ann Rev Biochem 56: 333–364, 1987Google Scholar
  44. 44.
    Wang KKW, Villalobo A, Roufogalis BD: Calmodulin-binding proteins as calpain substrates. Biochem J 262: 693–706, 1989Google Scholar
  45. 45.
    Molinari M, Anagli J, Carafoli E: PEST sequences do not influence substrate susceptibility to calpain proteolysis. J Biol Chem 270: 2032–2035, 1995Google Scholar
  46. 46.
    Carillo S, Pariat M, Steff AM, Roux P, Etienne-Julian M, Lorca T, Piechaczyk M: Differential sensitivity of Fos and Jun family members to calpain. Oncogene 9: 1679–1689, 1994Google Scholar
  47. 47.
    Di Lisa F, De Tullio R, Salamino F, Barbato R, Melloni E, Siliprandi N, Schiaffino S, Pontremoli S: Specific degradation of troponin T and I by m-calpain and its modulation by substrate phosphorylation. Biochem J 308: 57–61, 1995Google Scholar
  48. 48.
    Tischler ME, Fagan JM: Relationship of the reduction-oxidation state to protein degradation in skeletal and atrial muscle. Arch Biochem Biophys 217: 191–201, 1982Google Scholar
  49. 49.
    Rivett AJ: Regulation of intracellular protein turnover: covalent modification as a mechanism of marking proteins for degradation. Curr Topics Cell Regul 28: 291–337, 1986Google Scholar
  50. 50.
    Pierce GN, Dhalla NS: Mechanisms of the defect in cardiac myofibrillar function during diabetes. Am J Physiol 248: E170–E175, 1985Google Scholar
  51. 51.
    Belcastro AN, Machan C, Gilchrist JS: Diabetes enhances calpain degradation of cadiac myofibrils and easily releasable myofilaments. In: M Nagano, NS Dhalla (eds). The Diabetic Heart. Raven Press, New York, 1991, pp 301–310Google Scholar
  52. 52.
    Goll DE, Dayton WR, Singh I, Robson RM: Studies of the α-actinin/ actin interaction in the z-disk by using calpain. J Biol Chem 266: 8501–8510, 1991Google Scholar
  53. 53.
    Belcastro AN: Skeletal muscle calcium-activated neutral protease (calpain) with exercise. J Appl Physiol 746: 1381–1386, 1993Google Scholar
  54. 54.
    Reid WD, Huang J, Bryson S, Walker DC, Belcastro AN: Diaphragm injury and myofibrillar structure induced by resistive loading. J Appl Physiol 76: 176–184, 1994Google Scholar
  55. 55.
    Arthur GD, Belcastro AN: A calcium stimulated cysteine protease involved in isoproterenol induced cardiac hypertrophy. Mol Cell Biochem 176: 241–248, 1997Google Scholar
  56. 56.
    Duncan CJ: Role of calcium in triggering rapid ultrastructural damage in muscle: a study with chemically skinned fibres. J Cell Sci 87: 581–594, 1987Google Scholar
  57. 57.
    Duncan CJ, Jackson MJ: Different mechanisms mediate structural changes and intracellular enzyme efflux following damage to skeletal muscle. J Cell Sci 87: 183–188, 1987Google Scholar
  58. 58.
    Duan C, Delp MD, Hayes DA, Delp PD, Armstrong RB: Rat skeletal muscle mitochondrial [Ca2+] and injury from downhill walking. J Appl Physiol 68: 1241–1251, 1990Google Scholar
  59. 59.
    Tate CA, Bonner HW, Leslie SW: Calcium uptake in skeletal muscle mitochondria. Eur J Appl Physiol 39: 111–116, 1978Google Scholar
  60. 60.
    MacIntyre DL, Reid WD, McKenzie DC: Delayed muscle soreness. The inflammatory response to muscle injury and its clinical implications. Sports Med 20: 24–40, 1995Google Scholar
  61. 61.
    Duan C, Delp MD, Hayes DA, Delp PD, Armstrong RB: Skeletal muscle Ca2+ overload and injury from eccentric exercise. J Appl Physiol 68: 1241–1251, 1990Google Scholar
  62. 62.
    Armstrong RB, Duan C, Delp MD, Hayes DA, Glenn GM, Allen GD: Elevations in rat soleus muscle [Ca2+] with passive stretch. J Appl Physiol 74: 2990–2997, 1993Google Scholar
  63. 63.
    Warren GL, Lowe DA, Hayes DA, Farmer MA, Armstrong RB: Redistribution of cell membrane probes following contraction-induced injury of mouse soleus muscle. Cell Tissue Res 282: 311–320, 1995Google Scholar
  64. 64.
    Jones DA, Jackson MJ, McPhail G, Edwards RH: Experimental mouse muscle damage: the importance of external calcium. Clin Sci 66: 317–322, 1984Google Scholar
  65. 65.
    Byrd SK: Alterations in the sarcoplasmic reticulum: a possible link to exercise-induced muscle damage. Med Sci Sports Exerc 24: 531–536, 1992Google Scholar
  66. 66.
    Fitts RH, Kim DH, Witzmann FAA: The effects of prolonged activity on the sarcoplasmic reticulum and myofibrils of fast and slow skeletal muscle. Physiologist 22: 38, 1979Google Scholar
  67. 67.
    Vollestad NK, Sejerstad DM: Biochemical correlates of fatigue: a brief review. Eur J Appl Physiol 53: 336–347, 1988Google Scholar
  68. 68.
    Belcastro AN, MacLean I, Gilchrist J, Turcotte R, Wall S, Williamson SM: Coordination of Ca2+ regulating and Ca2+ regulated processes in the study of muscle function. Can J Appl Spt Sci 11: 11–15, 1986Google Scholar
  69. 69.
    Sembrowich WL, Wang E, Hutchinson TE, Johnson D: Electron microprobe analysis of fatiqued fast-and slow-twitch muscle. Int Ser Sport Sci Biochem Exer 13: 571–576, 1983Google Scholar
  70. 70.
    Somylo AV, Gonzalez-Serratos H, McClellan G, Shuman H, Borrero LM, Somlyo AP: Electron microprobe analysis of the sarcoplasmic reticulum and vacuolated t-tubule system of fatigued frog muscles. Ann NY Acad Sci 307: 232–234, 1978Google Scholar
  71. 71.
    Sembrowich WL, Gollnick PD: Calcium uptake by heart and skeletal muscle sarcoplasmic reticulum from exercised rats. Med Sci Sport 9: 64, 1977Google Scholar
  72. 72.
    Belcastro AN, Rossiter M, Low MP, Sopper MM: Calcium activation of sarcoplasmic reticulum ATPase following strenous activity. Can J Physiol Pharmacol 59: 1214–1218, 1981Google Scholar
  73. 73.
    Belcastro AN, Gilchrist J, Scrubb J: Function of skeletal muscle sarcoplasmic reticulum vesicles with exercise. J Appl Physiol 75: 2412–2418, 1993Google Scholar
  74. 74.
    Baracos VE, Greenberg RE, Goldberg AL: Influence of calcium and other divalent cations on protein turnover in rat skeletal muscle. Am J Physiol 250: E702–E710, 1986Google Scholar
  75. 75.
    Stauber WT: Eccentric action of muscles: physiology, injury and adaptation. Exerc Sport Sci Rev 17: 157–185, 1989Google Scholar
  76. 76.
    Pyne DB: Regulation of neutrophil function during exercise. Sports Med 17: 245–258, 1994Google Scholar
  77. 77.
    Camus G, Pincemail J, Ledent M, Juchmes-Ferir A, Lamy M, Deby-Dupont G, Deby C: Plasma levels of polymorphonuclear elastase and myeloperoxidase after uphill walking and downhill running at similar energy cost. Int J Sports Med 13: 443–446, 1992Google Scholar
  78. 78.
    Fielding RA, Manfredi TJ, Ding WJ, Fiatarone MA, Evans WJ, Cannon JG: Acute phase response in exercise III. Neutrophil and IL-1b accumulation in skeletal muscle. Am J Physiol 265: R166–172, 1993Google Scholar
  79. 79.
    Walker BAM, Fantone JC: The inflammatory response. In: LH Sigal, Y Ron (eds). Immunology and Inflammation: Basic Mechanisms and Clinical Consequences. McGraw Hill, New York, 1994, pp 359–386Google Scholar
  80. 80.
    Edwards SW: Biochemistry and Physiology of the Neutrophil. Cambridge University Press, Cambridge, 1994Google Scholar
  81. 81.
    Territo MC: Chemotaxis. In: MJ Cline (ed). Leukocyte Function. Churchill Livingstone, New York, 1981, pp 39–52Google Scholar
  82. 82.
    Bistrian BR, Schwartz J, Istfan NW: Cytokines, muscle proteolysis, and the catabolic response to infection and inflammation. Infect Inflam 200: 220–223, 1992Google Scholar
  83. 83.
    Kunimatsu M, Ma XJ, Ozaki Y, Narita M, Mizokami M, Sasaki M: Neutrophil chemotactic N-acetyl peptides from the calpain small subunit are also chemotactic for immunocytes. Biochem Mol Biol Int 35: 247–254, 1995Google Scholar
  84. 84.
    Kunimatsu M, Ma XJ, Ozaki Y, Nishimura J, Baba S, Sasaki M: Neutrophil responses induced by formyl and acetyl peptides with the N-terminal sequence of the calpain small subunit. Biochem Mol Biol Int 31: 477–484, 1993Google Scholar
  85. 85.
    Klebanoff SJ, Clark RA: The Neutrophil: Function and Clinical Disorders. North-Holland Biomedical Press, Amsterdam, 1978Google Scholar
  86. 86.
    Sasaki M, Kunimatsu M, Ohkubo I: Role of calpains and kininogens in inflammation. Acta Biol Hung 42: 231–42, 1991Google Scholar
  87. 87.
    Raj DA, Booker TS, Belcastro AN: The relationship between myeloperoxidase and calpain-like activity with exercise-induced muscle injury. Can J Appl Physiol 20: 42P, 1995Google Scholar
  88. 88.
    Berridge MJ: Calcium signaling and cell proliferation. BioEssays 17: 491–500, 1995Google Scholar
  89. 89.
    Reddy GPV: Cell cycle: regulatory events in G 1–S transition of mammalian cells. J Cell Biochem 54: 379–386, 1994Google Scholar
  90. 90.
    Schollmeyer JE: Calpain II involvement in mitosis. Science 240: 911–913, 1988Google Scholar
  91. 91.
    Schollmeyer JE: Possible role of calpain I and calpain II in differentiating muscle. Exp Cell Res 163: 413–422, 1986Google Scholar
  92. 92.
    Schollmeyer JE: Role of Ca2+ and Ca2+-activated protease in myoblast fusion. Exp Cell Res 162: 411–422, 1986Google Scholar
  93. 93.
    Kwak KB, Chung SS, Kim OM, Kang MS, Ha DB, Chung CH: Increase in the level of m-calpain correlates with the elevated cleavage of filamin during myogenic differentiation of embryonic muscle cells. Biochim Biophys Acta 1175: 243–249, 1993Google Scholar
  94. 94.
    Poussard S, Cottin P, Brustis JJ, Talmat S, Elamrani N, Ducastaing A: Quantitative measurement of calpain I and II mRNAs in differentiating rat muscle cells using a competitive polymerase chain reaction. Biochimie 75: 885–890, 1993Google Scholar
  95. 95.
    Elamrani N, Balcerzak D, Soriano M, Brustis JJ, Cottin P, Poussard S, Ducastaing A: Evidence for fibronectin degradation by calpain II. Biochimie 75: 849–853, 1993Google Scholar
  96. 96.
    Cottin P, Brustis JJ, Poussard S, Elamrani N, Broncard S, Ducastaing A: Ca2+-dependent proteinases (calpains) and muscle cell differentiation. Biochim Biophys Acta 1223: 170–178, 1994Google Scholar
  97. 97.
    Ebisui C, Tsujinaka T, Kido Y, Iijima S, Yano M, Shibata H, Tanaka T, Mori T: Role of intracellular proteases in differentiation of L6 myoblast cells. Biochem Mol Biol Int 32: 515–521, 1994Google Scholar
  98. 98.
    Mellgren RL: Calcium-dependent proteases: an enzyme system active at cellular membranes? FASEB J: 1110–1115, 1987Google Scholar
  99. 99.
    Suzuki K, Imajoh S, Emori Y, Kawasaki H, Minami Y: Activity regulation of calcium protease. In: G Weber (ed). Advances in Enzyme Regulation. Pergamon Press, Oxford UK, 1988, pp 153–169Google Scholar
  100. 100.
    Gates RE, King LEJ: Proteolysis of the epidermal growth factor by endogenous calcium-activated neutral protease from rat liver. Biochem Biophys Res Comm 113(1): 255–261, 1983Google Scholar
  101. 101.
    Murayama A, Fukai F, Murachi T: Action of calpain on the basic estrogen receptor molecule of porcine uterus. J Biochem 95: 1697–1704, 1984Google Scholar
  102. 102.
    Hayashi M, Inomata M, Nakamura M, Imahori K, Kawashima S: Hydrolysis of protamine by calcium-activated neutral protease. J Biochem 97: 1363–1370, 1985Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Angelo N. Belcastro
    • 1
  • Leann D. Shewchuk
    • 1
  • Daniel A. Raj
    • 1
  1. 1.School of Rehabilitation Sciences, Faculty of MedicineUniversity of British ColumbiaVancouverCanada

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