Identification of 1- and 3-methylhistidine as biomarkers of skeletal muscle toxicity by nuclear magnetic resonance-based metabolic profiling

Anal Biochem. 2011 Mar 1;410(1):84-91. doi: 10.1016/j.ab.2010.11.023. Epub 2010 Nov 19.


Nuclear magnetic resonance (NMR)-based metabolomic profiling identified urinary 1- and 3-methylhistidine (1- and 3-MH) as potential biomarkers of skeletal muscle toxicity in Sprague-Dawley rats following 7 and 14 daily doses of 0.5 or 1mg/kg cerivastatin. These metabolites were highly correlated to sex-, dose- and time-dependent development of cerivastatin-induced myotoxicity. Subsequently, the distribution and concentration of 1- and 3-MH were quantified in 18 tissues by gas chromatography-mass spectrometry. The methylhistidine isomers were most abundant in skeletal muscle with no fiber or sex differences observed; however, 3-MH was also present in cardiac and smooth muscle. In a second study, rats receiving 14 daily doses of 1mg/kg cerivastatin (a myotoxic dose) had 6- and 2-fold elevations in 1- and 3-MH in urine and had 11- and 3-fold increases in 1- and 3-MH in serum, respectively. Selectivity of these potential biomarkers was tested by dosing rats with the cardiotoxicant isoproterenol (0.5mg/kg), and a 2-fold decrease in urinary 1- and 3-MH was observed and attributed to the anabolic effect on skeletal muscle. These findings indicate that 1- and 3-MH may be useful urine and serum biomarkers of drug-induced skeletal muscle toxicity and hypertrophy in the rat, and further investigation into their use and limitations is warranted.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Creatine / metabolism
  • Creatine / urine
  • Dose-Response Relationship, Drug
  • Female
  • Magnetic Resonance Spectroscopy / methods*
  • Male
  • Metabolomics / methods*
  • Methylhistidines / metabolism*
  • Methylhistidines / pharmacokinetics
  • Methylhistidines / urine
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Muscular Diseases / chemically induced
  • Muscular Diseases / metabolism
  • Muscular Diseases / urine
  • Pyridines / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors


  • Biomarkers
  • Methylhistidines
  • Pyridines
  • 1-methylhistidine
  • cerivastatin
  • 3-methylhistidine
  • Creatine