Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle

Abstract

Morash AJ, Kotwica AO, Murray AJ. Tissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle. Am J Physiol Regul Integr Comp Physiol 305: R534 -R541, 2013. First published June 19, 2013 doi:10.1152/ajpregu.00510.2012.-Exposure to hypobaric hypoxia is sufficient to decrease cardiac PCr/ATP and alters skeletal muscle energetics in humans. Cellular mechanisms underlying the different metabolic responses of these tissues and the time-dependent nature of these changes are currently unknown, but altered substrate utilization and mitochondrial function may be a contributory factor. We therefore sought to investigate the effects of acute (1 day) and more sustained (7 days) hypoxia (13% O 2) on the transcription factor peroxisome proliferator-activated receptor ␣ (PPAR␣) and its targets in mouse cardiac and skeletal muscle. In the heart, PPAR␣ expression was 40% higher than in normoxia after 1 and 7 days of hypoxia. Activities of carnitine palmitoyltransferase (CPT) I and ␤-hydroxyacyl-CoA dehydrogenase (HOAD) were 75% and 35% lower, respectively, after 1 day of hypoxia, returning to normoxic levels after 7 days. Oxidative phosphorylation respiration rates using palmitoyl-carnitine followed a similar pattern, while respiration using pyruvate decreased. In skeletal muscle, PPAR␣ expression and CPT I activity were 20% and 65% lower, respectively, after 1 day of hypoxia, remaining at this level after 7 days with no change in HOAD activity. Oxidative phosphorylation respiration rates using palmitoyl-carnitine were lower in skeletal muscle throughout hypoxia, while respiration using pyruvate remained unchanged. The rate of CO2 production from palmitate oxidation was significantly lower in both tissues throughout hypoxia. Thus cardiac muscle may remain reliant on fatty acids during sustained hypoxia, while skeletal muscle decreases fatty acid oxidation and maintains pyruvate oxidation. fatty acids; mitochondrial respiration; hypoxia; metabolism; heart HYPOBARIC HYPOXIA elicits a myriad of physiological responses that aim to increase oxygen availability at the tissues or decrease tissue oxygen demand (42). Central to this response is an acute increase in cardiac output, which in the face of atmospheric hypoxia can lead to an inability to match oxygen demand at the heart tissue itself (17). In a study of humans returning from exposure to hypobaric hypoxia at high altitude, resting energy levels were maintained in the subjects' skeletal muscle (9), whereas their hearts showed impaired energetics as indicated by decreased PCr/ATP (17). The cellular mechanisms underlying the different responses of these two tissues are unknown; however, the process of metabolic remodelling may differ under hypoxic conditions, and it has been suggested that altered substrate selection and mitochondrial respiration may be key factors in this regard (23,38,50).In the healthy heart, 90% of ATP production is generated via mitochondrial oxidative phosphorylation with 60 -70% of that energy being derived from lipid oxidation (3...

HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology

“…This is notably illustrated by a decrease in carnitine palmitoyl transferase and hydroxyacyl-coenzyme A dehydrogenase activity that has frequently been reported ( Table 2). The overall effect of hypoxia logically resulted in a marked reduction of fatty acid oxidation after 1 week in hypoxic environment [66,67].…”

Hypoxia in skeletal muscles: from physiology to gene expression

“…Besides glycolysis, the increased pyruvate dehydrogenase kinase is considered as another way to compensate the decreased ATP production [55] . This response might be tissue specific since, in cardiac muscles, a decrease in pyruvate metabolism is reported [17] . Furthermore, Norrbom et al report an enhancement of fatty acid metabolism in skeletal muscles during acute hypoxia induced by exercise [60] , while Morash et al report a reduction of fatty acid oxidation in skeletal muscle during hypoxia [17] .…”

“…This response might be tissue specific since, in cardiac muscles, a decrease in pyruvate metabolism is reported [17] . Furthermore, Norrbom et al report an enhancement of fatty acid metabolism in skeletal muscles during acute hypoxia induced by exercise [60] , while Morash et al report a reduction of fatty acid oxidation in skeletal muscle during hypoxia [17] . These results suggest a potential role of fatty acid metabolism in energy rebalance during hypoxia.…”

“…Compared with other tissues such as brain, heart, which are oxygen-sensitive, skeletal muscles are relatively tolerant to hypoxia, probably due to the energy buffering system, the relatively less demand of oxygen and its accustom to hypoxia during physical exercise [17][18][19] . However, hypoxia still induces a number of responses in skeletal muscles.…”

The Discovery of Two Novel Biomarkers in a High-Fat Diet C56bl6 Obese Mouse Model for Non-Adipose Tissue: A Comprehensive LCMS Study at Hind Limb, Heart, Carcass Muscle, Liver, Brain, Blood Plasma and Food Composition Following a Lipidomics LCMS-Based Approach

“…Since the flux through the β-oxidation is high during normoxic conditions [23,24], fatty acids and their metabolites rapidly accumulate during anaerobiosis [46]. In addition, during hypoxia or ischemia, the cellular energy status may be affected.…”