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Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise.
Toxicol Sci 2017; 156(2):422-427TS

Abstract

The skeletal muscle (SKM) injury biomarkers, skeletal troponin I (sTnI), myosin light chain 3 (Myl3), and creatine kinase muscle isoform (Ckm) have been shown recently to be more sensitive and specific for monitoring drug-induced SKM injury than the conventional biomarkers, aspartate transaminase (AST) and creatine kinase (CK) enzymatic assays in rat toxicology studies. To evaluate the utility of these SKM biomarkers across species, they were assessed in 2 dog models: a drug-induced injury study in Beagle dogs and a 160 km endurance exercise run completed by Alaskan sled dogs. In the drug-induced injury model, mean sTnI and Myl3 plasma levels were 6- and 18-fold, respectively, compared with baseline as early as Study Day (SD) 15, while mean plasma AST and CK levels did not increase, and biopsy samples were non-remarkable for histopathology prior to SD 29 when degeneration was first noted. Peak group mean plasma responses over baseline for sTnI, Myl3, and Ckm biomarkers were 96-, 103-, and 11-fold, respectively, compared with 2.5-fold for AST and 3.8-fold for CK-enzymatic (CK-enz) assay. In the sled dog sustained exercise model, the peak response for all biomarkers was observed at the first sampling (2 h) after the completion of the run. The sTnI, Myl3, and Ckm mean fold peak values compared with baseline were 170-, 120-, and 150-fold, respectively, while AST increased 7-fold and CK-enz increased 29-fold. These findings support the conclusion that sTnI, Myl3, and Ckm are sensitive early tissue leakage biomarkers for monitoring SKM injury and effects of exercise in dog, extending their utility across preclinical species beyond the rat, and provide further support to investigate their translational utility to clinical trial settings to monitor for drug-induced SKM injury and ensure patient safety.

Authors+Show Affiliations

Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.Department of Safety Assessment and Laboratory Animal Resources, MRL, West Point, Pennsylvania 19486.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28115646

Citation

Vlasakova, Katerina, et al. "Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 156, no. 2, 2017, pp. 422-427.
Vlasakova K, Lane P, Michna L, et al. Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise. Toxicol Sci. 2017;156(2):422-427.
Vlasakova, K., Lane, P., Michna, L., Muniappa, N., Sistare, F. D., & Glaab, W. E. (2017). Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise. Toxicological Sciences : an Official Journal of the Society of Toxicology, 156(2), pp. 422-427. doi:10.1093/toxsci/kfw262.
Vlasakova K, et al. Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise. Toxicol Sci. 2017 04 1;156(2):422-427. PubMed PMID: 28115646.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Response of Novel Skeletal Muscle Biomarkers in Dogs to Drug-Induced Skeletal Muscle Injury or Sustained Endurance Exercise. AU - Vlasakova,Katerina, AU - Lane,Pamela, AU - Michna,Laura, AU - Muniappa,Nagaraja, AU - Sistare,Frank D, AU - Glaab,Warren E, PY - 2017/1/25/pubmed PY - 2018/1/18/medline PY - 2017/1/25/entrez KW - biomarkers KW - creatine kinase KW - dog. KW - myosin light chain 3 KW - skeletal muscle KW - skeletal troponin I SP - 422 EP - 427 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol. Sci. VL - 156 IS - 2 N2 - The skeletal muscle (SKM) injury biomarkers, skeletal troponin I (sTnI), myosin light chain 3 (Myl3), and creatine kinase muscle isoform (Ckm) have been shown recently to be more sensitive and specific for monitoring drug-induced SKM injury than the conventional biomarkers, aspartate transaminase (AST) and creatine kinase (CK) enzymatic assays in rat toxicology studies. To evaluate the utility of these SKM biomarkers across species, they were assessed in 2 dog models: a drug-induced injury study in Beagle dogs and a 160 km endurance exercise run completed by Alaskan sled dogs. In the drug-induced injury model, mean sTnI and Myl3 plasma levels were 6- and 18-fold, respectively, compared with baseline as early as Study Day (SD) 15, while mean plasma AST and CK levels did not increase, and biopsy samples were non-remarkable for histopathology prior to SD 29 when degeneration was first noted. Peak group mean plasma responses over baseline for sTnI, Myl3, and Ckm biomarkers were 96-, 103-, and 11-fold, respectively, compared with 2.5-fold for AST and 3.8-fold for CK-enzymatic (CK-enz) assay. In the sled dog sustained exercise model, the peak response for all biomarkers was observed at the first sampling (2 h) after the completion of the run. The sTnI, Myl3, and Ckm mean fold peak values compared with baseline were 170-, 120-, and 150-fold, respectively, while AST increased 7-fold and CK-enz increased 29-fold. These findings support the conclusion that sTnI, Myl3, and Ckm are sensitive early tissue leakage biomarkers for monitoring SKM injury and effects of exercise in dog, extending their utility across preclinical species beyond the rat, and provide further support to investigate their translational utility to clinical trial settings to monitor for drug-induced SKM injury and ensure patient safety. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/28115646/Response_of_Novel_Skeletal_Muscle_Biomarkers_in_Dogs_to_Drug_Induced_Skeletal_Muscle_Injury_or_Sustained_Endurance_Exercise_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfw262 DB - PRIME DP - Unbound Medicine ER -