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Genetic polymorphisms associated with exertional rhabdomyolysis

European Journal of Applied Physiology Aims and scope Submit manuscript

Abstract

Exertional rhabdomyolysis (ER) occurs in young, otherwise healthy, individuals principally during strenuous exercise, athletic, and military training. Although many risk factors have been offered, it is unclear why some individuals develop ER when participating in comparable levels of physical exertion under identical environmental conditions and others do not. This study investigated possible genetic polymorphisms that might help explain ER. DNA samples derived from a laboratory-based study of persons who had never experienced an episode of ER (controls) and clinical ER cases referred for testing over the past several years were analyzed for single nucleotide polymorphisms (SNPs) in candidate genes. These included angiotensin I converting enzyme (ACE), α-actinin-3 (ACTN3), creatine kinase muscle isoform (CKMM), heat shock protein A1B (HSPA1B), interleukin 6 (IL6), myosin light chain kinase (MYLK), adenosine monophosphate deaminase 1 (AMPD1), and sickle cell trait (HbS). Population included 134 controls and 47 ER cases. The majority of ER cases were men (n = 42/47, 89.4 %); the five women with ER were Caucasian. Eighteen African Americans (56.3 %) were ER cases. Three SNPs were associated with ER: CKMM Ncol, ACTN3 R577X, and MYLK C37885A. ER cases were 3.1 times more likely to have the GG genotype of CKMM (odds ratio/OR = 3.1, confidence interval/CI 1.33–7.10), 3.0 times for the XX genotype of ACTN3 SNP (OR = 2.97, CI 1.30–3.37), and 5.7 times for an A allele of MYLK (OR = 21.35, CI 2.60–12.30). All persons with HbS were also ER cases. Three distinct polymorphisms were associated with ER. Further work will be required to replicate these findings and determine the mechanism(s) whereby these variants might confer susceptibility.

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Fig. 1

Abbreviations

ACTN3 :

α-Actinin 3

AMPD1 :

Adenosine monophosphate deaminase 1, isoform M

ACE :

Angiotensin I converting enzyme

AFIP:

Armed Forces Institute of Pathology

χ 2 :

Chi-square test

CKMM :

Creatine kinase muscle isoform

CK:

Creatine kinase

ER:

Exertional rhabdomyolysis

Type II:

Fast twitch (Type II) skeletal muscle fibers

HWE:

Hardy–Weinberg equilibrium

HSPA1B :

Heat shock protein A1B

IL6 :

Interleukin 6

MYLK :

Myosin light chain kinase

RLC:

Myosin’s regulatory light chains

RFLP:

Restriction fragment length polymorphisms

HbS :

Sickle cell trait

SNP:

Single nucleotide polymorphisms

References

  • Aizawa H, Morita K, Minami H, Sasaki N, Tobise K (1995) Exertional rhabdomyolysis as a result of strenuous military training. J Neurol Sci 132:239–240

    Article  PubMed  CAS  Google Scholar 

  • Alpers JP, Jones LK Jr (2010) Natural history of exertional rhabdomyolysis: a population-based analysis. Muscle Nerve 42:487–491

    Article  PubMed  Google Scholar 

  • Armed Forces Health Surveillance Center (2011) Update: exertional rhabdomyolysis, active component, US Armed Forces, 2010. MSMR 18:9–11

    Google Scholar 

  • Armed Forces Health Surveillance Center (2012) Update: exertional rhabdomyolysis, active component, US Armed Forces, 2011. MSMR 19(3):17–19

    Google Scholar 

  • Banasik M, Kuzniar J, Kusztal M, Porazko T, Weyde W, Klinger M (2008) Myoglobinuria caused by exertional rhabdomyolysis misdiagnosed as psychiatric illness. Med Sci Monit 14(1):CS1–CS4

    PubMed  CAS  Google Scholar 

  • Berman Y, North KN (2010) A gene for speed: the emerging role of alpha-actinin-3 in muscle metabolism. Physiology (Bethesda) 25:250–259

    Article  CAS  Google Scholar 

  • Bessman SP, Geiger PJ (1981) Transport of energy in muscle: the phosphorylcreatine shuttle. Science 211:448–452

    Article  PubMed  CAS  Google Scholar 

  • Brancaccio P, Lippi G, Maffulli N (2010) Biochemical markers of muscular damage. Clin Chem Lab Med 48:757–767

    Article  PubMed  CAS  Google Scholar 

  • Brewster LM, Mairuhu G, Bindraban NR, Koopmans RP, Clark JF, van Montfrans GA (2006) Creatine kinase activity is associated with blood pressure. Circulation 114:2034–2039

    Article  PubMed  CAS  Google Scholar 

  • Brewster LM, Mairuhu G, Sturk A, van Montfrans GA (2007) Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 154:655–661

    Article  PubMed  CAS  Google Scholar 

  • Capacchione JF, Muldoon SM (2009) The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 109:1065–1069

    Article  PubMed  Google Scholar 

  • Chevion S, Moran DS, Heled Y, Shani Y, Regev G, Abbou B, Berenshtein E, Stadtman ER, Epstein Y (2003) Plasma antioxidant status and cell injury after severe physical exercise. Proc Natl Acad Sci USA 100:5119–5123

    Article  PubMed  CAS  Google Scholar 

  • Childers MK, McDonald KS (2004) Regulatory light chain phosphorylation increases eccentric contraction-induced injury in skinned fast-twitch fibers. Muscle Nerve 29:313–317

    Article  PubMed  CAS  Google Scholar 

  • Clarkson PM, Ebbeling C (1988) Investigation of serum creatine kinase variability after muscle-damaging exercise. Clin Sci (Lond) 75:257–261

    CAS  Google Scholar 

  • Clarkson PM, Hoffman EP, Zambraski E, Gordish-Dressman H, Kearns A, Hubal M, Harmon B, Devaney JM (2005) ACTN3 and MLCK genotype associations with exertional muscle damage. J Appl Physiol 99:564–569

    Article  PubMed  CAS  Google Scholar 

  • Contreras-Sesvold CL, Sambuughin N, Blokhin A, Deuster PA (2010) A protocol comparison for the analysis of heat shock protein A1B + A1538G SNP. Cell Stress Chaperones 15:205–209

    Article  PubMed  CAS  Google Scholar 

  • Deuster PA, O’Connor FG, Kenney K, Heled Y, Muldoon S, Contreras-Sesvold CL, Campbell WW (2009) Creatine kinase clinical considerations: ethnicity, gender and genetics. North Atlantic Treaty Organization: Research and Technology Organization; Human Factors and Medicine Pane. ftp.rta.nato.int Sofia, Bulgaria

  • Exantus J, Ranchin B, Dubourg L, Touraine R, Baverel G, Cochat P (2004) Acute renal failure in a patient with phosphofructokinase deficiency. Pediatr Nephrol 19:111–113

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Real JM, Broch M, Vendrell J, Gutierrez C, Casamitjana R, Pugeat M, Richart C, Ricart W (2000) Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 49:517–520

    Article  PubMed  CAS  Google Scholar 

  • Fischer S, Drenckhahn C, Wolf C, Eschrich K, Kellermann S, Froster UG, Schober R (2005) Clinical significance and neuropathology of primary MADD in C34-T and G468-T mutations of the AMPD1 gene. Clin Neuropathol 24:77–85

    PubMed  CAS  Google Scholar 

  • Gabardi S, Munz K, Ulbricht C (2007) A review of dietary supplement-induced renal dysfunction. Clin J Am Soc Nephrol 2:757–765

    Article  PubMed  CAS  Google Scholar 

  • Gennarelli M, Novelli G, Cobo A, Baiget M, Dallapiccola B (1991) 3′ creatine kinase (M-type) polymorphisms linked to myotonic dystrophy in Italian and Spanish populations. Hum Genet 87:654–656

    Article  PubMed  CAS  Google Scholar 

  • Gledhill RF, Van der Merwe CA, Greyling M, Van Niekerk MM (1988) Race–gender differences in serum creatine kinase activity: a study among South Africans. J Neurol Neurosurg Psychiatry 51:301–304

    Article  PubMed  CAS  Google Scholar 

  • Hains AD, Pannall PR, Bourne AJ, Carey WF, Disney AP, Black AB, Albertyn LA (1984) McArdle’s disease presenting with rhabdomyolysis. Aust N Z J Med 14:681–684

    Article  PubMed  CAS  Google Scholar 

  • Harrelson GL, Fincher AL, Robinson JB (1995) Acute exertional rhabdomyolysis and its relationship to sickle cell trait. J Athl Train 30:309–312

    PubMed  CAS  Google Scholar 

  • Heled Y, Bloom MS, Wu TJ, Stephens Q, Deuster PA (2007) CK-MM and ACE genotypes and physiological prediction of the creatine kinase response to exercise. J Appl Physiol 103:504–510

    Article  PubMed  CAS  Google Scholar 

  • Hsu YD, Lee WH, Chang MK, Shieh SD, Tsao WL (1997) Blood lactate threshold and type II fibre predominance in patients with exertional heatstroke. J Neurol Neurosurg Psychiatry 62:182–187

    Article  PubMed  CAS  Google Scholar 

  • Hubal MJ, Devaney JM, Hoffman EP, Zambraski EJ, Gordish-Dressman H, Kearns AK, Larkin JS, Adham K, Patel RR, Clarkson PM (2010) CCL2 and CCR2 polymorphisms are associated with markers of exercise-induced skeletal muscle damage. J Appl Physiol 108:1651–1658

    Article  PubMed  CAS  Google Scholar 

  • Kenney K, Landau ME, Gonzalez RS, Hundertmark J, O’Brien K, Campbell WW (2012) Serum creatine kinase after exercise: drawing the line between physiological response and exertional rhabdomyolysis. Muscle Nerve 45:356–362

    Article  PubMed  CAS  Google Scholar 

  • Landau ME, Kenney K, Deuster P, Campbell W (2012a) Exertional rhabdomyolysis: a clinical review with a focus on genetic influences. J Clin Neuromusc Dis 13:122–136

    Article  Google Scholar 

  • Landau ME, Kenney K, Deuster P, Gonzalez RS, Contreras-Sesvold C, Sambuughin N, O’Connor FG, Campbell WW (2012b) Investigation of the relationship between serum creatine kinase and genetic polymorphisms in military recruits. Mil Med 177:1359–1365

    PubMed  Google Scholar 

  • Lek M, Quinlan KG, North KN (2010) The evolution of skeletal muscle performance: gene duplication and divergence of human sarcomeric alpha-actinins. Bioessays 32:17–25

    Article  PubMed  CAS  Google Scholar 

  • Lofberg M, Jankala H, Paetau A, Harkonen M, Somer H (1998) Metabolic causes of recurrent rhabdomyolysis. Acta Neurol Scand 98:268–275

    Article  PubMed  CAS  Google Scholar 

  • Mahakkanukrauh A, Sangchan A, Mootsikapun P (2003) Exertional rhabdomyolysis following excessive exercise of university freshman cheer-training. J Med Assoc Thai 86:789–792

    PubMed  Google Scholar 

  • Makaryus JN, Catanzaro JN, Katona KC (2007) Exertional rhabdomyolysis and renal failure in patients with sickle cell trait: is it time to change our approach? Hematology 12:349–352

    Article  PubMed  CAS  Google Scholar 

  • Melli G, Chaudhry V, Cornblath DR (2005) Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine 84:377–385

    Article  PubMed  Google Scholar 

  • Meltzer HY, Holy PA (1974) Black–white differences in serum creatine phosphokinase (CPK) activity. Clin Chim Acta 54:215–224

    Article  PubMed  CAS  Google Scholar 

  • Mochizuki T, Tauxe WN, Perper JA (1990) Technetium-99 m MDP scintigraphy of rhabdomyolysis induced by exertional heat stroke: a case report. Ann Nucl Med 4:111–113

    Article  PubMed  CAS  Google Scholar 

  • Neal RC, Ferdinand KC, Ycas J, Miller E (2009) Relationship of ethnic origin, gender, and age to blood creatine kinase levels. Am J Med 122:73–78

    Article  PubMed  CAS  Google Scholar 

  • Newham DJ, Jones DA, Edwards RH (1983) Large delayed plasma creatine kinase changes after stepping exercise. Muscle Nerve 6:380–385

    Article  PubMed  CAS  Google Scholar 

  • Nosaka K, Clarkson PM (1996) Variability in serum creatine kinase response after eccentric exercise of the elbow flexors. Int J Sports Med 17:120–127

    Article  PubMed  CAS  Google Scholar 

  • Olerud JE, Homer LD, Carroll HW (1976) Incidence of acute exertional rhabdomyolysis. Serum myoglobin and enzyme levels as indicators of muscle injury. Arch Intern Med 136:692–697

    Article  PubMed  CAS  Google Scholar 

  • Patchett DC, Grover ML (2011) Mitochondrial myopathy presenting as rhabdomyolysis. J Am Osteopath Assoc 111:404–405

    PubMed  Google Scholar 

  • Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S (2009) The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet 76:564–568

    Article  PubMed  CAS  Google Scholar 

  • Santos J Jr (1999) Exertional rhabdomyolysis. Potentially life-threatening consequence of intense exercise. JAAPA 12:46–49 (53–45)

    PubMed  Google Scholar 

  • Sauret JM, Marinides G, Wang GK (2002) Rhabdomyolysis. Am Fam Physician 65:907–912

    PubMed  Google Scholar 

  • Sevketoglu E, Kural B, Beskardes AE, Hatipoglu S (2011) Exertional rhabdomyolysis after influenza A (H3N2) infection in a basketball player boy. Ann Trop Paediatr 31:93–96

    Article  PubMed  CAS  Google Scholar 

  • Sherry P (1990) Sickle cell trait and rhabdomyolysis: case report and review of the literature. Mil Med 155:59–61

    PubMed  CAS  Google Scholar 

  • Sherwood RA, Lambert A, Newham DJ, Wassif WS, Peters TJ (1996) The effect of eccentric exercise on serum creatine kinase activity in different ethnic groups. Ann Clin Biochem 33(Pt 4):324–329

    PubMed  CAS  Google Scholar 

  • Skenderi KP, Kavouras SA, Anastasiou CA, Yiannakouris N, Matalas AL (2006) Exertional rhabdomyolysis during a 246-km continuous running race. Med Sci Sports Exerc 38:1054–1057

    Article  PubMed  CAS  Google Scholar 

  • Stahl CE, Borlongan CV, Szerlip M, Szerlip H (2006) No pain, no gain—exercise-induced rhabdomyolysis associated with the performance enhancer herbal supplement ephedra. Med Sci Monit 12:CS81–CS84

    PubMed  Google Scholar 

  • Stull JT, Kamm KE, Vandenboom R (2011) Myosin light chain kinase and the role of myosin light chain phosphorylation in skeletal muscle. Arch Biochem Biophys 510:120–128

    Article  PubMed  CAS  Google Scholar 

  • Tanner CJ, Barakat HA, Dohm GL, Pories WJ, MacDonald KG, Cunningham PR, Swanson MS, Houmard JA (2002) Muscle fiber type is associated with obesity and weight loss. Am J Physiol Endocrinol Metab 282:E1191–E1196

    PubMed  CAS  Google Scholar 

  • Thompson HS, Maynard EB, Morales ER, Scordilis SP (2003) Exercise-induced HSP27, HSP70 and MAPK responses in human skeletal muscle. Acta Physiol Scand 178:61–72

    Article  PubMed  CAS  Google Scholar 

  • Tietjen DP, Guzzi LM (1989) Exertional rhabdomyolysis and acute renal failure following the army physical fitness test. Mil Med 154:23–25

    PubMed  CAS  Google Scholar 

  • Tsujino S, Shanske S, Carroll JE, Sabina RL, DiMauro S (1995) Double trouble: combined myophosphorylase and AMP deaminase deficiency in a child homozygous for nonsense mutations at both loci. Neuromuscul Disord 5:263–266

    Article  PubMed  CAS  Google Scholar 

  • United States Census Bureau (2012) The 2012 Statistical Abstract The National Data Book. In: Commerce USDo (ed). US Department of Commerce

  • van Adel BA, Tarnopolsky MA (2009) Metabolic myopathies: update 2009. J Clin Neuromusc Dis 10:97–121

    Article  Google Scholar 

  • Wilson IA, Brindle KM, Fulton AM (1995) Differential localization of the mRNA of the M and B isoforms of creatine kinase in myoblasts. Biochem J 308(Pt 2):599–605

    PubMed  CAS  Google Scholar 

  • Wu AHB, Smith A, Wians F (2009) Interpretation of creatine kinase and aldolase for statin-induced myopathy: reliance on serial testing based on biological variation. Clin Chim Acta 399:109–111

    Article  PubMed  CAS  Google Scholar 

  • Yamin C, Amir O, Sagiv M, Attias E, Meckel Y, Eynon N, Amir RE (2007) ACE ID genotype affects blood creatine kinase response to eccentric exercise. J Appl Physiol 103:2057–2061

    Article  PubMed  Google Scholar 

  • Yamin C, Duarte JA, Oliveira JM, Amir O, Sagiv M, Eynon N, Amir RE (2008) IL6 (−174) and TNFA (−308) promoter polymorphisms are associated with systemic creatine kinase response to eccentric exercise. Eur J Appl Physiol 104:579–586

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge that this research was funded by grants from the Uniformed Services University (R091CE) and the Comprehensive National Neuroscience Program (G191CR).

Conflict of interest

The views expressed are those of the authors and do not reflect the official position of the Uniformed Services University, Department of the Army, Department of the Air Force, Department of the Navy or the United States Department of Defense. In addition, the authors report no conflict of interest.

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Correspondence to Patricia A. Deuster.

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Communicated by Martin Flueck.

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Deuster, P.A., Contreras-Sesvold, C.L., O’Connor, F.G. et al. Genetic polymorphisms associated with exertional rhabdomyolysis. Eur J Appl Physiol 113, 1997–2004 (2013). https://doi.org/10.1007/s00421-013-2622-y

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