Mitochondrial dysfunction in the skeletal muscle is a major factor in the causation of insulin resistance and thus diabetes. The mitochondrial dysfunction is initiated by reduced energy demand of the muscle over a period of time. The energy demand in the muscle is primarily caused by three ATP utilizing processes: Na+-K+ ATPase that maintain the ion balance, myosin ATPase that mediate the contraction-relaxation process and Ca2+ ATPase that helps to uptake Ca2+ back into the sarcoplasmic reticulum causing relaxation. Out of these three, Ca2+-handling processes is especially important as the ATP used by this mechanism can be regulated by small peptide modulators like sarcolipin significantly manipulating whole body energy expenditure. We are interested to understand the alteration of such mechanisms in muscles of patients with type 2 diabetes. Further, if such alteration is correlated with progression of diabetes. Towards this we are trying to define the energy status of muscle and adipose tissues in obese, pre-diabetic and/or diabetic people in this part of the world.

Calsequestrin (CASQ) is a Ca2+ buffering protein found inside the SR of muscles; having two isoforms CASQ1 in skeletal muscles and CASQ2 in the cardiac muscle. Mutations in CASQ2 have been known to cause a form of cardiac arrhythmia called Catecholaminergic polymorphic ventricular tachycardia (CPVT). My earlier studies indicated that these mutations interfere with the Ca2+ buffering capacity and dynamics of CASQ2. The monomers of CASQ2 interact to form a front-to-front dimer and then establish back-to-back interactions to form tetramers. Further, interactions of these oligomers leadto formation of highly ordered polymer. But these CASQ2 polymers are very delicate and undergo rapid depolymerisation when Ca2+- concentration inside the SR drops during Ca2+-release effects. We are exploring the possibility of pharmacologically stabilizing the back-to-back interactions thereby correcting CPVT and related cardiac arrhythmia.