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

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 1α (PGC‐1α) gene was downregulated in CHF, as well as nuclear respiratory factor 2 and mitochondrial transcription factor A, which act downstream from PGC‐1α. Most interestingly, only the level of PGC‐1α 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‐1α appears as a potential modulator of muscle oxidative capacity under these experimental conditions.

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Moreover, CS activity increased progressively despite the progressive decrease in mitochondrial biogenesis and content across the 3 phenotypes. This is in contrast to what has been shown in systolic HF where CS activity is decreased along with the decrease in mitochondrial biogenesis and content 47. This may suggest that the decrease in CS activity occurs later in the progression to overt systolic dysfunction and HF.…”

Is defective electron transport at the hub of aging?

“…Some laboratories report no attenuation of respiratory complexes with age (Torii et al, 1992;Barazzoni et al, 2000;Kwong & Sohal, 2000), whereas others have observed decreased complex I and IV activities (Sugiyama et al, 1993;Andreu et al, 1998), transcript levels (Andreu et al, 1998;Hudson et al, 1998) and protein synthesis (Hudson et al, 1998). In rat models of congestive heart failure, declines in transcripts for subunits of complex IV and enzyme activity are associated with decreased levels of the nuclear factors PGC-1α, Tfam and NRF-2 (Garnier et al, 2003). Cardiac interfibrillar mitochondria located between the myofibrils exhibit lower protein yield and oxidative capacity in elderly rats.…”

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

“…18 Similarly, downregulation of PGC-1a in hypertrophic cardiac failure is responsible for apoptotic cell death of cardiac myocytes. 19,20 These effects might due to impaired mitochondrial function, and imply a strong antiapoptotic effect of the protein. However, the mechanisms linking PGC-1a-induced mitochondrial changes to decreased susceptibility to cell death are unknown.…”