Pdk-1/Hif-1α Ratios Define Geniohyoid Muscle Fiber Phenotypes

Abstract

Background: The relationships between muscle fiber-type expression and the ratio between pyruvate dehydrogenase kinase (Pdk)-1 and hypoxia inducible factor (Hif)-1α was investigated using Hif-1α heterozygous knockout (“Het”) mice. Because Pdk-1/Hif-1α ratio changes could alter skeletal muscle phenotypes following brief sustained hypoxia as demonstrated earlier, we aimed to examine if the genetically down-regulated Hif-1α level influences skeletal muscle phenotypes in an intermittent hypoxic (IH) condition. This query is important because upper airway dilating muscles in patients with obstructive sleep apnea who frequently exposed to IH conditions tend to have an increased Type II fibers with increased Hif-1α levels. Methods: Here, we examined whether Pdk-1/Hif-1 ratios play a role in Het Hif-1α KO mice when exposed to brief IH (altering ambient oxygen levels between 10.3% and 20.8% every 240s). We performed single fiber analysis and Western blots on the harvested geniohyoid (GH) muscle after IH treatment for 5h. Results: Wild-type (WT) GH muscles in mice contain muscle fibers composed of myosin heavy chain (MyHC) IIa and MyHC IIa/IIb proteins, as opposed to the GH muscle in Het mice expressing MyHC IIa, IIa/IIb as well as IIb (p<0.001). Fiber composition in WT GH showed no significant changes under IH. In Het mice, a higher proportion of MyHC IIb fibers were expressed, as the number of IIa fibers decreased (p< 0.05) in IH. Pdk-1/Hif-1α ratios in the Het-GH muscle did not alter significantly after 5h IH exposure. Conclusion: The increased numbers of glycolytic fibers with high Pdk-1/Hif-1 ratios resulted in Het-GH muscles being able to avoid excessive ‘oxidative stress’ under IH. However, Het-GH muscles might have become more fatigable after IH exposure, compared to WT mice, since Het-GH muscles after IH contain higher numbers of MyHC IIb-containing glycolytic fibers that are more fatigable in nature than WT-GH muscles.