The muscle fiber type–fiber size paradox: hypertrophy or oxidative metabolism?

An inverse relationship exists between striated muscle fiber size and its oxidative capacity. This relationship implies that muscle fibers, which are triggered to simultaneously increase their mass/strength (hypertrophy) and fatigue resistance (oxidative capacity), increase these properties (strength or fatigue resistance) to a lesser extent compared to fibers increasing either of these alone. Muscle fiber size and oxidative capacity are determined by the balance between myofibrillar protein synthesis, mitochondrial biosynthesis and degradation. New experimental data and an inventory of critical stimuli and state of activation of the signaling pathways involved in regulating contractile and metabolic protein turnover reveal: (1) higher capacity for protein synthesis in high compared to low oxidative fibers; (2) competition between signaling pathways for synthesis of myofibrillar proteins and proteins associated with oxidative metabolism; i.e., increased mitochondrial biogenesis via AMP-activated protein kinase attenuates the rate of protein synthesis; (3) relatively higher expression levels of E3-ligases and proteasome-mediated protein degradation in high oxidative fibers. These observations could explain the fiber type–fiber size paradox that despite the high capacity for protein synthesis in high oxidative fibers, these fibers remain relatively small. However, it remains challenging to understand the mechanisms by which contractile activity, mechanical loading, cellular energy status and cellular oxygen tension affect regulation of fiber size. Therefore, one needs to know the relative contribution of the signaling pathways to protein turnover in high and low oxidative fibers. The outcome and ideas presented are relevant to optimizing treatment and training in the fields of sports, cardiology, oncology, pulmonology and rehabilitation medicine

Een beertje kan al topvondst zijn

In het voormalige doorvoerkamp Westerbork graven archeologen sindsdeze week naar sporen van het dagelijks leven. ‘De vraag dient zich aanvan wie Westerbork eigenlijk is.’ Door Ana van Es en Maarten Keulemans

Novel Approaches to Treat Experimental Pulmonary Arterial Hypertension: A Review

Background. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current treatments can improve symptoms and reduce severity of the hemodynamic disorder but gradual deterioration in their condition often necessitates a lung transplant. Methods and Results. In experimental models of PAH, particularly the model of monocrotaline-induced pulmonary hypertension, efficacious treatment options tested so far include a spectrum of pharmacologic agents with actions such as anti-mitogenic, proendothelial function, proangiogenic, antiinflammatory and antioxidative. Emerging trends in PAH treatment are gene and cell therapy and their combination, like (progenitor) cells enriched with eNOS or VEGF gene. More animal data should be collected to investigate optimal cell type, in vitro cell transduction, route of administration, and number of cells to inject. Several recently discovered and experimentally tested interventions bear potential for therapeutic purposes in humans or have been shown already to be effective in PAH patients leading to improved life expectation and better quality of life. Conclusion. Since many patients remain symptomatic despite therapy, we should encourage research in animal models of PAH and implement promising treatments in homogeneous groups of PAH patients

Eicosapentaenoic acid incorporation in membrane phospholipids modulates receptor-mediated phospholipase C and membrane fluidity in rat ventricular myocytes in culture

The influence of increased incorporation of linoleic acid (18:2n-6) and eicosapentaenoic acid (20:5n-3) in membrane phospholipids on receptor-mediated phospholipase Cβ (PLC-β) activity in cultured rat ventricular myocytes was investigated. For this purpose, cells were grown for 4 days in control, stearic acid (18:0)/oleic acid (18:1n-9), 18:2n-6 and 20:5n-3 enriched media, and subsequently assayed for the basal- and phenylephrine- or endothelin-1-induced total inositol phosphate formation. The various fatty acid treatments resulted in the expected alterations of fatty acid composition of membrane phospholipids. In 18:2n-6-treated cells, the incorporation of this 18:2n-6 in the phospholipids increased from 17.1 mol % in control cells to 38.9 mol %. In 20:5n-3-treated cells, incorporation of 20: 5n-3 and docosapentaenoic acid (22:5n-3) in the phospholipids increased from 0.5 and 2.7 mol % in control cells to 23.2 and 9.7 mol %, respectively. When 20:5n-3-treated cells were stimulated with phenylephrine or endothelin-1, the inositolphosphate production decreased by 33.2% and increased by 43.4%, respectively, as compared to cells grown in control medium. No efffects were seen in 18:2n-6-treated cells. When 18:0/18:1n-9-treated cells were stimulated with endothelin-1, inositolphosphate formation increased by 26.4%, whereas phenylephrine-stimulated inositolphosphate formation was not affected. In saponin-permeabilized cells, that were pre-treated with 20:5n-3, the formation of total inositolphosphates after stimulation with GTPγS, in the presence of Ca2+, was inhibited 19.3%. This suggests that the 20:5n-3 effect on intact cardiomyocytes could be exerted either on the level of agonist-receptor, receptor-GTP-binding-protein coupling or GTP-binding-protein-PLC-β interaction. Investigation of the time course of saponin-induced permeabilization of the cardiomyocytes, measured by the release of lactate dehydrogenase, unmasked a slight decrease in the rate of permeabilization by 20:5n-3 pretreatment, indicating a protective effect. This led the authors to measure the cholesterol/phospholipid molar ratio, the double bond index of membrane phospholipids, and the membrane fluidity; the latter by using a diphenylhexatriene probe. In 20: 5n-3-pretreated cells, a strong increase in the cholesterol/phospholipid molar ratio (from 0.23 to 0.39), a marked increase in the double bond index (from 1.76 to 2.33), and a slight decrease in fluidity (steady-state anisotropy r(ss) of the diphenylhexatriene probe increased from 0.196 to 0.217) were observed. Thus, treatment of cardiomyocytes for 4 days with 20:5n-3, but not with 18:2n-6, causes alterations of receptor-mediated phospholipase Cβ activity. A causal relationship may exist between the 20:5 n-3-induced alterations of the physicochemical properties in the bilayer and of the agonist-stimulated phosphatidylinositol cycle activity

A refined radio-telemetry technique to monitor right ventricle or pulmonary artery pressures in rats: a useful tool in pulmonary hypertension research

Implantable radio-telemetry methodology, allowing for continuous recording of pulmonary haemodynamics, has previously been used to assess effects of therapy on development and treatment of pulmonary hypertension. In the original procedure, rats were subjected to invasive thoracic surgery, which imposes significant stress that may disturb critical aspects of the cardiovascular system and delay recovery. In the present study, we describe and compare the original trans-thoracic approach with a new, simpler trans-diaphragm approach for catheter placement, which avoids the need for surgical invasion of the thorax. Satisfactory overall success rates up to 75% were achieved in both approaches, and right ventricular pressures and heart and respiratory rates normalised within 2 weeks. However, recovery was significantly faster in trans-diaphragm than in trans-thoracic operated animals (6.4 ± 0.5 vs 9.5 ± 1.1 days, respectively; p < 0.05). Stable right ventricular pressures were recorded for more than 4 months, and pressure changes, induced by monocrotaline or pulmonary embolisms, were readily detected. The data demonstrate that right ventricular telemetry is a practicable procedure and a useful tool in pulmonary hypertension research in rats, especially when used in combination with echocardiography. We conclude that the described trans-diaphragm approach should be considered as the method of choice, for it is less invasive and simpler to perform

Evaluation of pulmonary arterial hypertension: invasive or noninvasive?

Vascular Biology and Interventio