The energetics of mechanical overload in heart and skeletal myocytes
Willem van der Laarse received a Master degree in Medical Biology in 1980 and a PhD in Experimental Zoology at the University of Amsterdam in 1986. He was appointed assistant professor at the Laboratory for Physiology of the VU University in 1988. He is principle investigator or project leader of projects dealing with muscle energetics (funded by NWO, VWS, NHS, FBW VU, ICaR VU, ZON MW or STW).
The energetics of mechanical overload in heart and skeletal myocytes is the main research topic. The working hypothesis is that chronically increased workload of a myocyte initially improves its power output, but may eventually lead to mitochondrial dysfunction and reduced performance or even myocyte death. We investigate this process at all levels (from man to molecule and in different species) but for mechanistic studies focus on the level of the myocyte and mitochondria. Our aim is to discover when and why mitochondria fail, and to explore possibilities to delay, prevent, or restore failure. Increasing the myoglobin concentration, inhibition of monoamine oxidase-A, or restoring cardiolipin metabolism, is subject of investigation.
He investigated metabolic fluxes in single myocytes during the development of fatigue, developed a culture system for mature single myocytes, and discovered the inverse relationship between maximum metabolic power and myocyte size. This relationship implies that oxygen diffusion from the blood to the mitochondria limits the adaptation of myocytes to increased load, and provides explanations for the transition of myocardial hypertrophy to chronic heart failure and performance in sports. He developed histochemical methods for screening metabolic characteristics in tiny muscle preparations (mass 0.2 mg), e.g. papillary muscles, muscle biopsies or isolated myocytes. He participates in applying the new methods clinically and in sports.
Selection of recent publications
Balestra GM, Mik EG, Eerbeek O, Specht PAC, van der Laarse WJ, Zuurbier CJ (2015) Increased in vivo mitochondrial oxygenation with right ventricular failure induced by pulmonary hypertension. Mitochondrial inhibition as driver of cardiac failure? Respiratory Research in press.
RT Jaspers, J Testerink, B Della Gaspera, C Chanoine, CP Bagowski, WJ van der Laarse (2014) Increased oxidative metabolism and myoglobin expression in zebrafish muscle during chronic hypoxia. Biology Open 3, 718-727.
Van Eif VWW, Bogaards SJP, van der Laarse WJ (2014) Intrinsic cardiac adrenergic (ICA) cell density and MAO-A activitiy in failing rat hearts. Journal of Muscle Research and Cell Motility, 35, 47-53.
Wüst RCI, van der Laarse WJ, Rossiter HB (2013) On-off asymmetries in oxygen consumption kinetics of single Xenopus laevis skeletal muscle fibres suggest higher-order control. Journal of Physiology 591, 731-744.
Ruiter G, Wong YY, de Man FS, Handoko ML, Jaspers RT, Postmus PE, Westerhof N, Niessen HWM, van der Laarse WJ, Vonk Noordegraaf A. (2013) Right ventricular oxygen supply parameters are decreased in human and experimental pulmonary hypertension. Journal of Heart and Lung Transplantation 32, 231-240.
Wong YY, Ruiter G, Lubberdink M, Raijmakers P, Knaapen P, Marcus JT, Boonstra A, Lammertsma AA, Westerhof N, van der Laarse WJ, Vonk Noordegraaf A (2011) Right ventricular failure in idiopathic pulmonary hypertension is associated with inefficient myocardial oxygen utilization. Circulation Heart Failure 4, 700-706.
Wong YY, Handoko ML, Mouchaers KTB, de Man FS, Vonk Noordegraaf A, van der Laarse WJ (2010) Reduced mechanical efficiency of rat papillary muscles related to degree of hypertrophy of cardiomyocytes. American Journal of Physiology Heart Circulation Physiology 298, H1190-H1197.
Ongoing research projects
Causes of reduced myocardial efficiency. In the experimental model of pulmonary hypertension we are studying why myocardial efficiency decreases. Work and oxygen consumption of papillary muscles are used to calculate efficiency and blockers are used to identify the causes of reduced efficiency. We investigate in particular why oxygen is not predominantly used for contraction in the failing heart.
Myoglobin expression. One way to prevent mitochondrial failure and to prevent changes in cardiolipin metabolism is to prevent hypoxia in myocytes or radical stress. In theory, this is possible by increasing the myoglobin concentration in the cell. The myoglobin concentration can decrease in hypertrophying hearts of experimental models and pulmonary hypertensive patients (possibly due to oxidative stress and iron deficiency). We explore possibilities to enhance myoglobin expression (in collaboration with Dr RT Jaspers, FBW and Dr FM Vaz, AMC).
Mitochondrial oxygen tension. We are exploring possibilities to determine the mitochondrial oxygen tension by means of near infrared spectroscopy (in collaboration with Dr J de Ruiter FBW), 18FAZA (in collaboration with the departments Pulmonology and Nuclear Medicine VUmc), pimonidazole binding, protoprophyrin IX phosphorescence (in collaboration with Dr CJ Zuurbier, AMC) and mathematical modeling.