Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function

Zungu, Makhosazane; Alcolea, Maria P.; García-Palmer, Francisco J.; Young, Martin E.; Essop, M. Faadiel

doi:10.1152/ajpheart.00806.2006

Cited by 20 publications

(18 citation statements)

References 34 publications

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“…Ratios of plantaris muscle mass to body mass were also similar in control and hypoxic rats: 1.04 Ϯ 0.17 and 1.02 Ϯ 0.05 mg/g, respectively. That the rats were really hypoxic was reflected by the higher hematocrit than control rats (49.9 Ϯ 0.8 vs. 58.9 Ϯ 0.9%, P Ͻ 0.001) as well as elevated right ventricular systolic pressure (from 15 Ϯ 32 to 74 Ϯ 11 mmHg in controls vs. hypoxic rats, P Ͻ 0.001), and right ventricular hypertrophy (from 0.75 Ϯ 0.15 to 1.02 Ϯ 0.12 g/g body wt, P Ͻ 0.001), similar to that reported previously in hypobaric hypoxia (80).…”

Section: Resultssupporting

confidence: 86%

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia

Wüst

Jaspers²,

Heijst³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic exposure to hypoxia is associated with muscle atrophy (i.e., a reduction in muscle fiber cross-sectional area), reduced oxidative capacity, and capillary growth. It is controversial whether these changes are muscle and fiber type specific. We hypothesized that different regions of the same muscle would also respond differently to chronic hypoxia. To investigate this, we compared the deep (oxidative) and superficial (glycolytic) region of the plantaris muscle of eight male rats exposed to 4 wk of hypobaric hypoxia (410 mmHg, Po(2): 11.5 kPa) with those of nine normoxic rats. Hematocrit was higher in chronic hypoxic than control rats (59% vs. 50%, P < 0.001). Using histochemistry, we observed 10% fiber atrophy (P < 0.05) in both regions of the muscle but no shift in the fiber type composition and myoglobin concentration of the fibers. In hypoxic rats, succinate dehydrogenase (SDH) activity was elevated in fibers of each type in the superficial region (25%, P < 0.05) but not in the deep region, whereas in the deep region but not the superficial region the number of capillaries supplying a fiber was elevated (14%, P < 0.05). Model calculations showed that the region-specific alterations in fiber size, SDH activity, and capillary supply to a fiber prevented the occurrence of anoxic areas in the deep region but not in the superficial region. Inclusion of reported acclimatization-induced increases in mean capillary oxygen pressure attenuated the development of anoxic tissue areas in the superficial region of the muscle. We conclude that the determinants of tissue oxygenation show region-specific adaptations, resulting in a marked differential effect on tissue Po(2).

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Section: Resultssupporting

confidence: 86%

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia

Wüst

Jaspers²,

Heijst³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…The regulation of mitochondrial biogenesis and function by O 2 concentration has been previously observed in other animal tissues (19,60). Different O 2 concentrations may thus lead to different mitochondrial content in placental cells.…”

Section: Discussionmentioning

confidence: 65%

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Mandò

Palma

Stampalija

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

159

132

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Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called “placental insufficiency”, originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 ( NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus.

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“…In agreement, we recently demonstrated the coordinate induction of several genes regulating mitochondrial respiratory capacity, and increased mitochondrial DNA (mtDNA) content in the hypertrophied RV of rats exposed to 2 weeks of hypobaric hypoxia [3]. Transcript levels of nuclear respiratory factor 1 (NRF-1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), key transcriptional modulators of mitochondrial biogenesis, were increased in the hypertrophied RV but not the left ventricle (LV).…”

Section: Introductionmentioning

confidence: 55%

“…The hypoxic groups were housed inside a lexan chamber (45 kPa—11% O 2 ) (SciTech, Cape Town, South Africa) for 4 weeks as described previously [3], and compared to age-matched normoxic controls. On the last day of the experiments, animals were anesthetized with sodium pentobarbital (100 mg kg −1 i.p.)…”

Section: Methodsmentioning

confidence: 99%

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Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

et al. 2008

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Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats were exposed to 4 weeks CHH (11% O2) versus normoxic controls. RV/body weight ratio increased (P < 0.001 vs. control) while RV systolic and developed pressures were higher. However, LV systolic and developed pressures were significantly reduced. Mitochondrial O2 consumption was sustained in the hypertrophied RV, ADP/O increased (P < 0.01 vs. control) and proton leak significantly decreased. Conversely, LV mitochondrial O2 consumption was attenuated (P < 0.05 vs. control) and proton leak significantly increased. In parallel, expression of mitochondrial regulators was upregulated in the hypertrophied RV but not the LV. Our data show that the hypertrophied RV induces expression of mitochondrial regulatory genes linking respiratory capacity and enhanced efficiency to sustained contractile function.

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Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function

Cited by 20 publications

References 34 publications

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia

Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia

Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

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