Physiological effects of Plaat1 deficiency in mice

Introduction: Cardiolipin is produced de novo in an immature form, and must be remodeled to contain a fatty acyl profile that is functionally appropriate for the mitochondria in a specific tissue. We have recently discovered that phospholipase A and acyltransferase 1 (PLAAT1) has transacylase activity using monolysocardiolipin as an acyl acceptor, and phosphatidylcholine as an acyl donor, and that cells overexpressing PLAAT1 have higher levels of total cardiolipin, supporting a role for this enzyme in cardiolipin remodeling in vivo. We have generated Plaat1 global knockout mice ( Plaat1-/-) to study the role of this enzyme in whole body physiology. Objectives and methods: The objective of this study was to perform an initial physiological characterization of Plaat1-/- mice, with an emphasis on measures related to mitochondrial function. Activity levels, oxygen utilization, carbon dioxide production, respiratory exchange ratio (RER), and exercise capacity were measured and compared between Plaat1-/- and wildtype mice within sexes. Hypotheses:: We anticipate that altered cardiolipin remodeling due to Plaat1 deficiency will adversely affect mitochondrial function, resulting in changes in bioenergetic metabolism and exercise capacity. As compared to controls, we hypothesize that Plaat1-/- mice will have reduced activity levels and impaired exercise tolerance, but increased oxygen consumption rates and carbon dioxide production, with an elevated RER due to dependance on glycolysis. Increased heat production is also predicted due to an expected increased dissipation of the proton gradient. Results: Male Plaat1-/- mice had 42.1% ± 17.2% lower rearing activity over 24 hours compared to wildtype mice (n=6-8, P<0.05), but no differences in X- or Y-directional locomotor activity, while female Plaat1-/- mice did not differ from their wildtype ( Wt) littermates in these measures. However, Female Plaat1-/- mice had 31.9% ± 14.4% lower oxygen utilization (P<0.05), 34.3% ± 11.5% lower carbon dioxide production (P<0.05), and 45.8% ± 13.9% lower heat production (P<0.01) over 24 h when compared to Wt controls. Both male and female Plaat1-/- mice ran significantly shorter distances in a treadmill time-to-exhaustion test (P<0.05). Male Plaat1-/- mice had a mean run time of 32.4±2.3 minutes (min) before exhaustion compared to Wt littermates (35.8±2.3 min), while female Plaat1-/- mice had mean run times of 34.6±2.1 min compared to Wt littermates (38.3±1.9 min). Interestingly, however, when mice were subjected to two treadmill tests, 1-hour apart, male Wt mice displayed significantly decreased performance from their initial test (-6.7% ± 2.3%), but Plaat1-/- mice did not. Conclusions: Our initial physiological characterization demonstrates differences in behaviour, respiration, and exercise tolerance in both males and females deficient in Plaat1, supporting a role for this enzyme in whole body bioenergetic metabolism and exercise tolerance. This work is supported by the Barth Syndrome Foundation, and the Natural Sciences and Engineering Research Council of Canada (NSERC). R.E.D. was a recipient of an Early Investigator Award from the Canadian Lipoprotein Conference. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.