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- Onderdeel:faculteit der gedrags- en bewegingswetenschappen ( sectie physiology )
My main interest is in studying determinants of the contractile characteristics of muscle (i.e. muscle peak and steady state power and the length range of active force exertion). Normally the force that a muscle can exert is strictly regulated to movement in daily live. However, this appears not to be the case in chronic diseases of the heart and respiratory muscles or in neuromuscular disorders such a Duchenne dystrophy and cerebral pareses. These pathologies are all associated with muscle weakness, which is sometimes length-dependent. Therefore my second interest is in the basic regulatory mechanisms underlying adaptation. I focus on the following questions: 1) What are the mechanical and metabolic stimuli for adaptation of muscle size and oxidative capacity and 2) via which signaling pathways are these stimuli regulating synthesis and degradation of contractile and mitochondrial proteins? These processes are investigated at different levels of organization: 1) the myoblast in vitro, 2) the isolated mature muscle fiber (ex vivo culture of Xenopus muscle fibres), (3) whole muscle in situ and in vivo (mouse, rat, Xenopus and human).
Adaptation of muscle fiber size by mechanotransduction, expression of growth factors and therole of the extracellular matrix
Mechanical loading is a major stimulus for muscle hypertrophy and addition of sarcomeres in series. The mechanisms via which muscle fibers sense mechanical stimuli and how these stimuli regulate the rate of protein synthesis via their downstream signaling pathways is still an enigma. Evidence suggests that the extracellular matrix plays an important role in the force transmission from muscle fiber to bone (myofascial force transmission). We are currently testing the hypothesis that myofascial pathways are involved in activating muscle stem cells (satellite cells) and biochemical signaling pathways regulating mRNA transcription, translation and degradation of proteins. As mechanical loading of muscle fibers stimulates the expression of growth factors (e.g. insulin-like growth factors and myostatin) and cytokines (interleuking-6 and adiponectin) in muscle fibers and these factors have a strong ability to alter the rates of synthesis and/or degradation of muscle proteins, these factors receive particular interest. We use ex vivo and in vivo models to test the independent effects of particular stimuli as well as their interplay.
Adaptation of the oxidative capacity
The most important determinant of steady state power of muscle (or fatigability) is the mitochondrial density in the muscle fibers. The trade off of a high oxidative capacity is a limitation of the cross-sectional size of a muscle fiber. Muscle fiber size and mitochondrial density are inversely related. We investigate the mechanisms underlying the interactions between the regulation of muscle fiber size and mitochondrial density.
I am involved in several clinical projects. We investigate muscle geometry in children with neurological disorders such as cerebral pareses and brachial plexus injuries. We developed a novel 3D ultrasound technique for standardized in vivo measurement of the muscle geometry. Further we investigate how muscle size and oxidative capacity adapt in patients suffering from cachexia and chronic inflammatory diseases such as heart failure and metabolic syndrome and how training may counteract these adaptations.