Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles - PubMed (original) (raw)

Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles

A Garnier et al. J Physiol. 2003.

Abstract

Congestive heart failure (CHF) induces alterations in energy metabolism and mitochondrial function that span cardiac as well as skeletal muscles. Whether these defects originate from altered mitochondrial DNA copy number and/or mitochondrial gene transcription is not known at present, nor are the factors that control mitochondrial capacity in different muscle types completely understood. We used an experimental model of CHF induced by aortic banding in the rat and investigated mitochondrial respiration and enzyme activity of biochemical mitochondrial markers in cardiac, slow and fast skeletal muscles. We quantified mitochondrial DNA (mtDNA), expression of nuclear (COX IV) and mitochondrial (COX I) encoded cytochrome c oxidase subunits as well as nuclear factors involved in mitochondrial biogenesis and in the necessary coordinated interplay between nuclear and mitochondrial genomes in health and CHF. CHF induced a decrease in oxidative capacity and mitochondrial enzyme activities with a parallel decrease in the mRNA level of COX I and IV, but no change in mtDNA content. The expression of the peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1 alpha) gene was downregulated in CHF, as well as nuclear respiratory factor 2 and mitochondrial transcription factor A, which act downstream from PGC-1 alpha. Most interestingly, only the level of PGC-1 alpha expression was strongly correlated with muscle oxidative capacity in cardiac and skeletal muscles, both in healthy and CHF rats. Mitochondrial gene transcription is reduced in CHF, and PGC-1 alpha appears as a potential modulator of muscle oxidative capacity under these experimental conditions.

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Figures

Figure 1

Figure 1. Enzymatic activities and mitochondrial function in left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated and CHF rats

CS, citrate synthase; COX, cytochrome c oxidase; mi-CK, mitochondrial creatine kinase and formula image, maximal respiration rate. Values are means ±

s.e.m

. (n = 11). *P < 0.05; **P < 0.01; ***,†††P < 0.001 versus respective Sham group (*) or versus Sham LV (†).

Figure 2

Figure 2. Southern blot analysis of total DNA from left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated (S) and CHF rats

A, representative Southern blots for each muscle type with signals resulting from mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). A positive control corresponding to a plasmid carrying sequence complementary to the mitochondrial probe was included and provided a signal at 4365 bp. B, mtDNA-to-nDNA ratio was determined after quantification of each signal. Values are means ±

s.e.m

. (n = 11).

Figure 4

Figure 4. Real-time quantitative RT-PCR analysis of mRNA expression of peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 DNA-binding subunit α (NRF-2α) and mitochondrial transcription factor A (mtTFA) in left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated and CHF rats

Results are given as means ±

s.e.m

. of values normalized to β-actin transcription and multiplied by total RNA (mg wet weight)−1. *,†P < 0.05; **,††P < 0.01; ***,†††P < 0.001 versus respective Sham group (*) or versus Sham LV (†).

Figure 3

Figure 3. Real-time quantitative RT-PCR analysis of mRNA expression of mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit I (COX I) and nuclear DNA (nDNA)-encoded cytochrome c oxidase subunit IV (COX IV) in left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated and CHF rats

A, results are given as means ±

s.e.m

. of values normalized to β-actin transcription and multiplied by total RNA (mg wet weight)−1. *,†P < 0.05; **,††P < 0.01; ***,†††P < 0.001 versus respective Sham group (*) or versus Sham LV (†). B, correlations between the mRNA levels of COX I or COX IV and PGC-1α (peroxisome proliferator activated receptor gamma co-activator 1α). r, the correlation coefficient; P, the statistical significance.

Figure 5

Figure 5. Correlations between the mRNA expression level of PGC-1α and enzymatic activities of citrate synthase (CS), cytochrome c oxidase (COX), mitochondrial creatine kinase (mi-CK) or maximal respiration rate () in left ventricle (LV), soleus (SOL) and gastrocnemius (GAS) of sham-operated and CHF rats

r, the correlation coefficient; P, the statistical significance.

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