MUSCLE RHYTHMS

 

 

                                                                                             Paul de Goede                                                                                           p.de.goede@nin.knaw.nl

 

 

 Supervisors: Andries Kalsbeek & Chun-Xia Yi                              

Mitochondria are the cellular organelles that provide the main energy production of mammalian cells through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Mitochondria provide energy as needed by the cellular physiology and since the metabolic needs of cells are not static, adequate feedback mechanisms are necessary to ensure efficient energy homeostasis. A major influence on energy demand is the active or inactive phase of an organism. This active/inactive or sleep/wake rhythm is controlled by the biological clock. For example, through this biological clock most mammals, including humans, ready themselves for sleep as the night falls by lowering their heart rate and body temperature and by switching from carbohydrates to lipids as their main metabolic fuel. Alike most mammalian cell types, also within mitochondria daily rhythms have been found in protein activity, levels of metabolites that are important during energy production such as NAD+ and ATP, as well as in the TCA cycle and the oxidative phosphorylation rate.

Nowadays the majority of the global population eats and sleeps at irregular times and thus disobeys to the biological clock, possibly with detrimental effects for health and well-being. Indeed, human studies have found that a misalignment of the biological clock system, for example as a result of eating at irregular times, can lead to disturbances in glucose metabolism. It is therefore not unexpected that night-shift workers have an increased risk of type 2 diabetes mellitus (T2DM). T2DM is characterized by lower glucose uptake as a result of insulin insensitivity. During early stages of T2DM insulin production is increased in an attempt to maintain euglycemia, but as the disease progresses insulin production fails and hyperglycemia develops.

With this project we attempt to identify the changes in mitochondrial functioning resulting from shift work. The prime focus will be on mitochondrial functioning in skeletal muscle, since muscle is the major tissue for insulin stimulated glucose uptake. It is thus far unknown if shift work results in alterations in the mitochondrial rhythms in skeletal muscle. Hence, it is also unknown if mitochondria will parallel the changes in skeletal muscle seen after disturbing the muscle peripheral clock, or that such disturbances can lead to an additional level of misalignment, namely between the organ (muscle) and its organelles (mitochondria). To investigate this, time restricted feeding, e.g. feeding only during the inactive phase, will be used as an animal model to identify how shift work affects mitochondrial metabolism in muscle. First we will identify which mitochondrion-related genes in the skeletal muscle show an altered gene expression as a result of shift work and diet composition. At a later stage of the project changes in glucose tolerance and insulin sensitivity as a result of shift work will be analyzed. Finally, mitochondrion-related genes or their proteins identified in the first part of the project will be targeted in an attempt to restore normal glucose metabolism.

 

 Rey, G., & Reddy, A. B. (2013). Rhythmic Respiration. Science (New York, N.Y.), 342(6158), 570–571. http://doi.org/10.1126/science.1246658