Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin... Show moreSkeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short -chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mito-chondrial fatty-acid oxidation. Here we address the interplay between butyrate and the long-chain fatty acid palmitate and investigate how transcription, signalling and metabolism are integrated to result in the butyrate -induced skeletal muscle metabolism remodelling. Butyrate enhanced insulin sensitivity in palmitate-treated, insulin-resistant C2C12 cells, as shown by elevated insulin receptor 1 (IRS1) and pAKT protein levels and Slc2a4 (GLUT4) mRNA, which led to a higher glycolytic capacity. Long-chain fatty-acid oxidation capacity and other functional respiration parameters were not affected. Butyrate did upregulate mitochondrial proteins involved in its own oxidation, as well as concentrations of butyrylcarnitine and hydroyxybutyrylcarnitine. By knocking down the gene encoding medium-chain 3-ketoacyl-CoA thiolase (MCKAT, Acaa2), butyrate oxidation was inhibited, which amplified the effects of the SCFA on insulin sensitivity and glycolysis. This response was associated with enhanced HDAC inhibition, based on histone 3 acetylation levels. Butyrate enhances insulin sensitivity and induces glycolysis, without the requirement of upregulated long-chain fatty acid oxidation. Butyrate catabolism functions as an escape valve that attenuates HDAC inhibition. Thus, inhibition of butyrate oxidation indirectly prevents insulin resistance and stimulates glycolytic flux in myotubes treated with butyrate, most likely via an HDAC-dependent mechanism. Show less
Sarcopenia in old age has been associated with a higher mortality, poor physical functioning, poor outcome of surgery and higher drug toxicity. There is no general consensus on the definition of... Show moreSarcopenia in old age has been associated with a higher mortality, poor physical functioning, poor outcome of surgery and higher drug toxicity. There is no general consensus on the definition of sarcopenia. The aim of the research presented in this thesis was to assess the implications of the use of different diagnostic criteria for sarcopenia, and to define the most accurate criteria for sarcopenia. Currently used diagnostic criteria for sarcopenia can be divided into criteria based on (1) low muscle mass, (2) low muscle strength, and (3) low walking speed. This thesis describes how muscle mass can be further divided into relative muscle mass and absolute muscle mass. A higher body or fat mass is associated with a lower relative muscle mass and with a higher absolute muscle mass. Higher relative muscle mass at old age is associated with better physical performance and with less insulin resistance. It is suggested to reserve the term sarcopenia to describe a low muscle mass and dynapenia to describe a low muscle strength. Most importantly, this research illustrates that it is impossible to compare studies about sarcopenia in scientific literature due to the use of different diagnostic criteria for sarcopenia. Show less
