Limited impact of myoglobin knockout on metabolic phenotype in mice fed a high fat diet

Authors: ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); RUTKOWSKY - University Of California, Davis; TOLENTINO, TODD - University Of California, Davis; RAMSEY, JON - University Of California, Davis; KENT LLOYD, K.C. - University Of California, Davis; CHINTAPALLI, SREE VAMSEE - Arkansas Children'S Nutrition Research Center (ACNC); OLFERT, MARK - West Virginia University; BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC); Ferruzzi, Mario

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 12/27/2019
Publication Date: N/A
Citation: N/A

Interpretive Summary:

Technical Abstract: Myoglobin (Mb) functions as an O2 carrying protein in muscle and heart, supporting oxidative metabolism of long-chain fatty acids (LCFAs) and other fuels. Studies by our group and others have revealed that oxygenated Mb also serves as an acylcarnitine and LCFA binding protein, suggesting a role in lipid sequestration, trafficking and fatty acid oxidation (FAO) in Type 1 muscle fibers and in cardiomyocytes. Consistent with this concept, Flogel et al (1) found that Mb-deficient cardiac extracts had increased glycolytic substrate utilization compared to WT (wildtype) cardiac preparations. In the current study, a new Mb KO mouse was produced using CRISPR/Cas9 genome editing in C57BL/6N mice, and KO confirmed by Western blot of muscle and heart tissues. We hypothesized that Mb KO mice challenged with a high fat diet (HFD: 45% kcal) would have dysregulated muscle FAO, resulting in glucose intolerance and a whole-body shift in fuel utilization that would be exacerbated under cold conditions (in which there is increased reliance on FAO). Body weight and food intake were measured 3 times/wk starting at weaning. At 5 wk old, prior to HFD, male and female Mb KO and WT littermates had their metabolic rate (MR) and respiratory exchange ratio (RER) measured via indirect calorimetry at 10C and 22C (3 d/temp). Mice were then fed a HFD through age 19 wk, with MR and RER measured at 11 and 17 wk, and GTT and ITT performed at 15 and 16 wk, respectively. Mb KO did not significantly affect body weight gain, cumulative energy intake, glucose tolerance, or insulin sensitivity. Female Mb KO mice were slightly heavier and exhibited significantly more body fat at 19 wk of age when compared to their same-sex WT littermates. Female Mb KO mice at 4-5 wk of age (before being fed a HFD) tended to exhibit increased average RER suggesting more glycolytic substrate utilization compared to their same sex WT littermates. This was not evident in older female mice fed a HFD. Male Mb KO and WT mice did not have different average RER when fed a chow diet or HFD. Conclusion: Contrary to our hypothesis, the lack of whole body Mb under HFD or cold conditions did not result in gross metabolic shifts or perturbations as measured by indirect calorimetry, GTT or ITT. In addition, the current results and those from the Mb KO literature make it clear that Mb is not essential for survival. This could signal that compensatory mechanisms exist to ensure O2 delivery and oxidative metabolism of lipids in muscle. To this end, we are currently determining if increased capillarity, tissue lipidomics modifications, or fiber type switching are evident in Mb KO mice.