Biphasic response of skeletal muscle mitochondria to chronic cardiac pressure overload - role of respiratory chain complex activity.

Pressure overload induced heart failure affects cardiac mitochondrial function and leads to decreased respiratory capacity during contractile dysfunction. A similar cardiac mitochondrial dysfunction has been demonstrated by studies which induce heart failure through myocardial infarction or pacing. These heart failure models differ in their loading conditions to the heart and show nevertheless the same cardiac mitochondrial changes. Based on these observations we speculated that a workload independent mechanism may be responsible for the impairment in mitochondrial function after pressure overload, which may then also affect the skeletal muscle. We aimed to characterize changes in mitochondrial function of skeletal muscle during the transition from pressure overload (PO) induced cardiac hypertrophy to chronic heart failure. PO by transverse aortic constriction caused compensated hypertrophy at 2 weeks, HF with normal ejection fraction (EF) at 6 and 10 weeks, and hypertrophy with reduced EF at 20 weeks. Cardiac output was normal at all investigated time points. PO did not cause skeletal muscle atrophy. Mitochondrial respiratory capacity in soleus and gastrocnemius muscles showed an early increase (up to 6 weeks) and a later decline (significant at 20 weeks). Respiratory chain complex activities responded to PO in a biphasic manner. At 2 weeks, activity of complexes I and II was increased. These changes pseudo-normalized within the 6-10 week interval. At 20 weeks, all complexes showed reduced activities which coincided with clinical heart failure symptoms. However, both protein expression and supercomplex assembly (Blue-Native gel) remained normal. There were also no relevant changes in mRNA expression of genes involved in mitochondrial biogenesis. This temporal analysis reveals that mitochondrial function of skeletal muscle is changed early in the development of pressure overload induced heart failure without being directly influenced by an increased loading condition. The observed early increase and the later decline in respiratory capacity can be explained by concomitant activity changes of complex I and complex II and is not due to differences in gene expression or supercomplex assembly.

Schrepper A ，Schwarzer M ，Schöpe M ，Amorim PA ，Doenst T ... -  《-》

Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload.

Doenst T ，Pytel G ，Schrepper A ，Amorim P ，Färber G ，Shingu Y ，Mohr FW ，Schwarzer M ... -  《-》

Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure.

Li XM ，Ma YT ，Yang YN ，Liu F ，Chen BD ，Han W ，Zhang JF ，Gao XM ... -  《-》

Induction of heart failure by minimally invasive aortic constriction in mice: reduced peroxisome proliferator-activated receptor γ coactivator levels and mitochondrial dysfunction.

Mitochondrial dysfunction has been suggested as a potential cause for heart failure. Pressure overload is a common cause for heart failure. However, implementing pressure overload in mice is considered a model for compensated hypertrophy but not for heart failure. We assessed the suitability of minimally invasive transverse aortic constriction to induce heart failure in C57BL/6 mice and assessed mitochondrial biogenesis and function. Minimally invasive transverse aortic constriction was performed through a ministernotomy without intubation (minimally invasive transverse aortic constriction, n = 68; sham operation, n = 43). Hypertrophy was assessed based on heart weight/body weight ratios and histologic analyses, and contractile function was assessed based on intracardiac Millar pressure measurements. Expression of selected metabolic genes was assessed with reverse transcription-polymerase chain reaction and Western blotting. Maximal respiratory capacity (state 3) of isolated mitochondria was measured with a Clark-type electrode. Survival was 62%. Within 7 weeks, minimally invasive transverse aortic constriction induced significant hypertrophy (heart weight/body weight ratio: 10.08±0.28 mg/g for minimally invasive transverse aortic constriction vs 4.66±0.07 mg/g for sham operation; n=68; P<.01). Fifty-seven percent of mice undergoing minimally invasive transverse aortic constriction displayed signs of heart failure (pleural effusions, dyspnea, weight loss, and dp/dtmax of 3114±422 mm Hg/s, P<.05). All of them had heart weight/body weight ratios of greater than 10. Mice undergoing minimally invasive transverse aortic constriction with heart weight/body weight ratios of less than 10 had normal contractile function (dp/dtmax of 6471±292 mm Hg/s vs dp/dtmax of 6933±205 mmHg/s in sham mice) and no clinical signs of heart failure. The mitochondrial coactivator peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α) was downregulated in failing hearts only. PGC-1α and fatty acid oxidation gene expression were also decreased in failing hearts. State 3 respiration of isolated mitochondria was significantly reduced in all hearts subjected to pressure overload. Contractile dysfunction and heart failure can be induced in wild-type mice by means of minimally invasive aortic constriction. Pressure overload-induced heart failure in mice is associated with mitochondrial dysfunction, as characterized by downregulation of PGC-1α and reduced oxidative capacity.

Faerber G ，Barreto-Perreia F ，Schoepe M ，Gilsbach R ，Schrepper A ，Schwarzer M ，Mohr FW ，Hein L ，Doenst T ... -  《-》

Overt expression of AP-1 reduces alpha myosin heavy chain expression and contributes to heart failure from chronic volume overload.

Freire G ，Ocampo C ，Ilbawi N ，Griffin AJ ，Gupta M ... -  《-》