Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

Abstract

In mice, genetic background is known to influence various parameters, including cardiac function. Its impact on cardiac energy substrate metabolism-a factor known to be closely related to function and contributes to disease development-is, however, unclear. This was examined in this study. In commonly used control mouse substrains SJL/JCrNTac, 129S6/SvEvTac, C57Bl/6J, and C57Bl/6NCrl, we assessed the functional and metabolic phenotypes of 3-mo-old working mouse hearts perfused ex vivo with physiological concentrations of 13C-labeled carbohydrates (CHO) and a fatty acid (FA). Marked variations in various functional and metabolic flux parameters were observed among all mouse substrains, although the pattern observed differed for these parameters. For example, among all strains, C57Bl/6NCrl hearts had a greater cardiac output (+1.7-fold vs. SJL/JCrNTac and C57Bl/6J; P < 0.05), whereas at the metabolic level, 129S6/SvEvTac hearts stood out by displaying (vs. all 3 strains) a striking shift from exogenous FA (∼−3.5-fold) to CHO oxidation as well as increased glycolysis (+1.7-fold) and FA incorporation into triglycerides (+2-fold). Correlation analyses revealed, however, specific linkages between 1) glycolysis, FA oxidation, and pyruvate metabolism and 2) cardiac work, oxygen consumption with heart rate, respectively. This implies that any genetically determined factors affecting a given metabolic flux parameter may impact on the associated functional parameters. Our results emphasize the importance of selecting the appropriate control strain for cardiac metabolic studies using transgenic mice, a factor that has often been neglected. Understanding the molecular mechanisms underlying the diversity of strain-specific cardiac metabolic and functional profiles, particularly the 129S6/SvEvTac, may ultimately disclose new specific metabolic targets for interventions in heart disease.

Differences in Cell-Type–Specific Responses to Angiotensin II Explain Cardiac Remodeling Differences in C57BL/6 Mouse Substrains

“…However, a recent study reported that the cardiac output of C57BL/6N male mice is higher than that of their C57BL/6J counterparts. 5 Likewise, the effects of transverse aortic constriction on survival and the remodeling of left ventricles (LV) are much greater in C57BL/6N than in C57BL/6J mice. 6 Thus, evidence indicates that genetic drift can significantly alter cardiac phenotypes in the established C57BL/6 inbred strain.…”

“…All computations were done with the R/Maanova package v.1.16.0. 5 For Real-Time quantitative PCR (RT-qPCR), samples containing 250-500ng of total RNA were reverse-transcribed (RT) using 200U of Superscript II reverse transcriptase (InVitrogen), as per the manufacturer's protocol. For samples containing smaller amounts of RNA, cDNA was generated from 10 ng of total RNA using the QuanTitect® reverse transcription kit (Qiagen).…”

Mouse Strain Impacts Fatty Acid Uptake and Trafficking in Liver, Heart, and Brain: A Comparison of C57BL/6 and Swiss Webster Mice

“…Furthermore, when 129S6 are fed a high-fat diet, gene expression of acylCoA oxidase 1 (Acox1) is reduced, a protein which traffics fatty acids towards β-oxidation, however, under the same dietary conditions in BALB/C mice there is no change in expression [56]. Interestingly, in an ex vivo working heart model, C57BL/6 mice had increased Acox1 expression as compared to 129/SvEvTac mouse heart, and as a result had decreased incorporation of oleic acid into TAG pools and more was utilized for β-oxidation than in 129/SvEvTac mouse heart [14]. Collectively, these studies demonstrate that observations in one mouse strain are not directly applicable to another strain, and support our supposition that for lipid metabolism, observations between mouse strains are not interchangeable.…”

“…Appreciating differences in characteristics between mouse strains to leverage the advantages and minimize potential pitfalls is an important consideration in experimental design [34]. For instance, C57BL/6 mice are commonly utilized in a substantial share of the scientific literature and are often used to study lipid metabolism, including studies on the efficacy of n-3 fatty acids on inflammation and injury [11,12,14,35,36]. On the other hand, SW mice are have been used in the pharmacology of fatty acid metabolism such as effects of pyridine exposure and highfat diets on lipid metabolism [37][38][39].…”

“…Brain-and heart-fatty acid binding protein (FABP) were isolated from the brain of SW mice [10], while C57BL/6 mice are often used to study n-3 lipid metabolism and its potential benefits after ischemia and spinal cord injury [11][12][13] Further, hearts of C57BL/6 mice have decreased incorporation of exogenous radiolabeled oleic acid as compared to several other inbred strains as a result of increased mRNA expression of acyl-CoA oxidase 1 (Acox1) [14]. Interestingly, several inbred and outbred mouse strains including C57BL/6 and CD-1:SW have a mutation in the gene encoding for secretory group II phospholipase A 2 , with C57BL/6 mice having a homozygous frameshift mutation in the sPLA 2 gene, while CD-1:SW mice were heterozygous for this same mutation [15].…”