Ca2+ fluxes and insulin action in cardiac and skeletal muscles

Obesity and type 2 diabetes are major and rapidly increasing health problems in society. They are associated with several life-threatening conditions, including heart and renal failure, and damage to the nervous system. An inability of cells to respond normally to insulin, insulin resistance, is a key feature in obesity and type 2 diabetes.

Ca2+ is a versatile messenger that regulates diverse cellular functions such as fertilization, electrical signaling, contraction, synaptic transmission, gene transcription, hormonal signaling, metabolism, and cell death. To exert these diverse effects, duration, amplitude and spatial distribution of Ca2+ need to be tightly regulated. The role of Ca2+ in insulin signaling under normal conditions and in association with insulin resistance is uncertain.

This thesis focuses on Ca2+ fluxes and insulin action in cardiac and skeletal muscles. In the first two papers we examined the effect of insulin on Ca2+ homeostasis in normal, freshly isolated mouse ventricular cardiomyocytes and how Ca2+ handling was changed in an animal model of obesity and insulin resistance, ob/ob mice. Ob/ob cardiomyocytes showed prolonged electrically evoked Ca2+ transients and impaired mitochondrial Ca2+ handling, which resulted in extra Ca2+ transients that may predispose for arrhythmias in vivo. Moreover, we observed decreased ion fluxes through canonical transient receptor potential 3 (TRPC3) channels, which may affect intracellular Ca2+ homeostasis and hence cellular function.

In the following two papers, we investigated the role of Ca2+ in insulin-mediated glucose uptake in adult skeletal muscles. Increased Ca2+ influx in the presence of insulin potentiated glucose uptake in muscles from both normal and ob/ob mice, whereas decreased Ca2+ influx was associated with decreased insulinmediated glucose uptake. In addition, TRPC3 protein expression was knocked down using a novel transfection technique with small interfering RNA coupled to carbon nanotubes, which resulted in large decreases in diacylglycerol-induced Ca2+ influx and insulin-mediated glucose uptake. Insulin-mediated glucose uptake occurs via the glucose transporter 4 (GLUT4) that was found to co-localize with TRPC3 in the t-tubular system, which is considered to be the predominant site of glucose uptake in skeletal muscle.

Taken together, these studies shed light on how insulin and Ca2+ interact in signaling in cardiac and skeletal muscles. In the heart, components and channels that alter intracellular Ca2+ handling and might be involved in the development of acute cardiac failure in insulin resistant conditions have been identified. Further, we demonstrate that Ca2+ is important for insulin-mediated glucose uptake. Thus, the present data identify specific sites for therapeutic intervention in the treatment of conditions associated with insulin resistance.

List of scientific papers

I. Fauconnier J, Lanner JT, Zhang SJ, Tavi P, Bruton JD, Katz A, Westerblad H (2005). Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice. Diabetes. 54(8): 2375-81.
https://pubmed.ncbi.nlm.nih.gov/16046304

II. Fauconnier J, Lanner JT, Sultan A, Zhang SJ, Katz A, Bruton JD, Westerblad H (2007). Insulin potentiates TRPC3-mediated cation currents in normal but not in insulin-resistant mouse cardiomyocytes. Cardiovasc Res. 73(2): 376-85. Epub 2006 Oct 27
https://pubmed.ncbi.nlm.nih.gov/17156765

III. Lanner JT, Katz A, Tavi P, Sandström ME, Zhang SJ, Wretman C, James S, Fauconnier J, Lännergren J, Bruton JD, Westerblad H (2006). The role of Ca2+ influx for insulin-mediated glucose uptake in skeletal muscle. Diabetes. 55(7): 2077-83.
https://pubmed.ncbi.nlm.nih.gov/16804078

IV. Lanner JT, Bruton JD, Assefaw-Redda Y, Andronache Z, Zhang SJ, Severa D, Zhang ZB, Melzer W, Zhang SL, Katz A, Westerblad H (2008). Insulin resistance is associated with decreased TRPC3-mediated ion fluxes in adult skeletal muscle cells. [Submitted]

V. Lanner JT, Bruton JD, Katz A, Westerblad H (2008). Ca(2+) and insulin-mediated glucose uptake. Curr Opin Pharmacol. 8(3): 339-45. Epub 2008 Mar 5
https://pubmed.ncbi.nlm.nih.gov/18321782