Metabolic physiology and skeletal muscle phenotypes in male and female myoglobin knockout mice

Authors: ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); OLFERT, MARK - West Virginia University; RUTKOWSKY, JENNIFER - University Of California, Davis; CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); WILLIS, BRANDON - University Of California, Davis; BLACKBURN, MICHAEL - University Arkansas For Medical Sciences (UAMS); WILLIAMS, D. KEITH - University Arkansas For Medical Sciences (UAMS); O’REILLY, JULIANA - West Virginia University; TOLENTINO, TODD - University Of California, Davis; LLOYD, K.C. KENT - University Of California, Davis; Ferruzzi, Mario

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2021
Publication Date: 7/1/2021
Citation: Ono-Moore, K., Olfert, M., Rutkowsky, J.M., Chintapalli, S.V., Willis, B., Blackburn, M.L., Williams, D., O'Reilly, J., Tolentino, T., Lloyd, K., Adams, S.H. 2021. Metabolic physiology and skeletal muscle phenotypes in male and female myoglobin knockout mice. American Journal of Physiology - Endocrinology and Metabolism. 321(1):E63-E79. https://doi.org/10.1152/ajpendo.00624.2020.
DOI: https://doi.org/10.1152/ajpendo.00624.2020

Interpretive Summary: Myoglobin (Mb) is an important regulator of oxygen bioavailability in muscle and heart tissues, especially as external oxygen levels drop (e.g., during hypoxia development). Robust binding of long-chain fatty acid lipids and their derivatives to Mb, and enhanced sugar (glucose) metabolism in mouse hearts that lack Mb, suggests additional roles in muscle metabolism and fuel selection. To evaluate this, we measured energy expenditure (EE), respiratory exchange ratio (RER, a measure of which fuel is being used in the body [sugar, protein, fats]), body weight gain and body fat, glucose tolerance and insulin sensitivity in Mb knockout (Mb-/-) and control wildtype (WT) mice challenged with a high fat diet (HFD, 45% of calories). In males and females aged 5-6, 11-12, and 17-18 wk, there were no genotype effects on RER, EE, or food intake. RER and EE during a cold challenge, and glucose and insulin tolerance, were not different compared to within-sex WT controls. At ~18 and ~19 wk of age, female Mb-/- body fat was ~42-48% higher vs. WT (p=0.1). Since Mb is thought to control tissue oxygen status, loss of Mb might trigger adaptations that increase blood delivery to tissues in order to compensate. Capillarity indices were significantly increased in Mb-/-, specifically in high oxidative tissues soleus and deep gastrocnemius muscles. The results indicate that Mb loss does not have a major impact on whole-body glucose homeostasis, EE, RER, or response to a cold challenge in mice. However, the greater body fat in female Mb-/- mice indicates a sex-specific effect of Mb KO on fat storage and feed efficiency. This study illustrates that myoglobin, long thought to play an important role in regulating muscle and heart energy metabolism, may have other more subtle roles that remain the subject future experiments.

Technical Abstract: Myoglobin (Mb) is an important regulator of O2 bioavailability in type I muscle and heart during hypoxia development. Mb also plays a role in regulating cellular NO pools. Robust binding of long-chain fatty acids and long-chain acylcarnitines to Mb, and enhanced glucose metabolism in hearts of Mb knockout (KO) mice, suggests additional roles in muscle intermediary metabolism and fuel selection. To evaluate this hypothesis, we measured energy expenditure (EE), respiratory exchange ratio (RER), body weight gain and adiposity, glucose tolerance and insulin sensitivity in Mb knockout (Mb-/-) and wildtype (WT) mice challenged with a high fat diet (HFD, 45% of calories). In males (n=10/genotype) and females (n=9/genotype) aged 5-6, 11-12, and 17-18 wk, there were no genotype effects on RER, EE, or food intake. RER and EE during cold 10 degree C, 72 h), and glucose and insulin tolerance, were not different compared to within-sex WT ontrols. At ~18 and ~19 wk of age, female Mb-/- adiposity was ~42-48% higher vs. WT females p=0.1). Transcriptomics analyses (whole gastrocnemius, soleus) revealed few consistent changes, with the notable exception of a 20% drop in soleus transferrin receptor (Tfrc) mRNA. capillarity indices were significantly increased in Mb-/-, specifically in Mb-rich soleus and deep gastrocnemius. The results indicate that Mb loss does not have a major impact on whole-body glucose homeostasis, EE, RER, or response to a cold challenge in mice. However, the greater adiposity in female Mb-/- mice indicates a sex-specific effect of Mb KO on fat storage and feed efficiency.