Plasma 2-hydroxyglutarate, a promising prognostic biomarker candidate for skeletal muscle injury in Fischer 344 rats

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  • Obayashi Hisakuni
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University Research Function, Daiichi-Sankyo Co., Ltd.
  • Kobayashi Naoko
    Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.
  • Nezu Yoshikazu
    Rare Disease Laboratories, Daiichi-Sankyo Co., Ltd.
  • Yamoto Takashi
    Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd.
  • Shirai Mitsuyuki
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University
  • Asai Fumitoshi
    Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Azabu University

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<p>Previously, we have demonstrated the potential of plasma 2-hydroxyglutarate (2HG) as an easily detectable biomarker for skeletal muscle injury in rats. Here, we examined whether plasma 2HG was superior to conventional skeletal muscle damage biomarkers, including aspartate aminotransferase (AST), creatine kinase (CK), and skeletal muscle-type CK isoenzyme (CK-MM) levels, in rats. Skeletal muscle injury was induced in 4- or 9-week-old male Fischer 344 rats by cerivastatin (CER) or tetramethyl-p-phenylenediamine (TMPD) administration. Plasma 2HG levels were measured on days 4, 8, and 11 (CER group) and at 6 and 24 hr post-administration (TMPD group). Plasma AST, CK, and CK-MM activities and histopathological changes in the rectus femoris muscle were evaluated at the study endpoints. In the CER group, AST, CK, and CK-MM increased in 4- and 9-week-old rats, whereas increases in CK (4- and 9-week-old rats) and CK-MM (4-week-old rats) were not obvious in the TMPD group. In both 4- and 9-week-old rats, plasma 2HG increased on day 8 and at 24 hr post-administration in the CER and TMPD groups, respectively. Histopathological analysis revealed myofiber vacuolation and necrosis in both groups. The histopathological damage to the rectus femoris muscle was more severe in the CER than in the TMPD group. Increased plasma 2HG was associated with CER- and TMPD-induced skeletal muscle injuries in rats and was not affected by age differences or repeated blood collection. The results suggest that plasma 2HG is superior to CK and CK-MM as a biomarker for mild skeletal muscle injury.</p>

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