Abstract
Sex differences in cardiac physiology are getting increased attention. This study assessed whether isolated, permeabilized cardiomyocytes from male and female C57BL/6 mice differ in terms of their respiration with multiple substrates and overall intracellular diffusion restriction estimated by the apparent ADP-affinity of respiration. Using respirometry, we recorded 1) the activities of respiratory complexes I, II and IV, 2) the respiration rate with substrates fuelling either complex I, II, or I + II, and 3) the apparent ADP-affinity with substrates fuelling complex I and I + II. The respiration rates were normalized to protein content and citrate synthase (CS) activity. We found no sex differences in CS activity (a marker of mitochondrial content) normalized to protein content or in any of the respiration measurements. This suggests that cardiomyocytes from male and female mice do not differ in terms of mitochondrial respiratory capacity and apparent ADP-affinity. Pyruvate modestly lowered the respiration rate, when added to succinate, glutamate and malate. This may be explained by intramitochondrial compartmentalization caused by the formation of supercomplexes and their association with specific dehydrogenases. To our knowledge, we show for the first time that the apparent ADP-affinity was substrate-dependent. This suggests that substrates may change or regulate intracellular barriers in cardiomyocytes.
Highlights
In recent years there has been an increased focus on sex differences in cardiac physiology and pathology
When citrate synthase (CS) activity was normalized to protein content, there was no difference between males and females
Our main finding is that the respiration of permeabilized cardiomyocytes from healthy C57BL/6 mice in the presence of substrates that activate both complexes I and II did not differ between males and females
Summary
In recent years there has been an increased focus on sex differences in cardiac physiology and pathology. Females have a higher capacity for fatty acid oxidation, whereas males have a higher glucose utilization[2] It is unclear whether mitochondrial regulation and respiration differ between sexes. One study found higher activities of complexes III and IV in young, male rats, but no difference in the respiration rates measured with different substrates[4]. A third study found that the activities of complexes I, II and IV do not differ between sexes in either young or old rats, but there is a transitional sex difference in the apparent ADP affinity as it declines with age[6] The latter (the apparent ADP-affinity) estimates the overall diffusion restriction in cardiomyocytes. We recorded the ADP-dependency of respiration with only glutamate and malate (in order to compare with previous results) as well as with glutamate, malate, pyruvate, and succinate to fully activate respiration as in[11]
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