Alam, Nasreen; (1998) Malonyl-CoA metabolism in skeletal muscle. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Three skeletal muscle fibre types (type I, type IIa and type IIb) were assayed for the presence of the following enzymes ATP-citrate lyase, citrate-dependent acetyl-CoA carboxylase, fatty acid synthase and malonyl-CoA decarboxylase. All activities were present in each of the muscle fibre types studied. A cytosolic activity of malonyl-CoA decarboxylase would appear to offer a feasible route for the disposal of malonyl-CoA in skeletal muscle. Rat soleus muscle strips were incubated with 5mM glucose followed by measurements of tissue contents of malonyl-CoA, long chain fatty acyl-CoA and carnitine esters. Alternatively muscle strips were incubated with 5mM glucose and 0.2mM palmitate followed by measurements of [14C] palmitate CO2 formation from exogenous palmitate or from fatty acids released from prelabelled glycerolipids. Etomoxir at high concentrations (150µM) significantly decreased the malonyl-CoA content by 50% and at low concentrations (50 & 100µM) had no effect on malonyl-CoA. Etomoxir had no effect on the total long chain ester pool but significantly increased long chain acyl-CoA and decreased the ratio of acyl-carnitine/acyl-CoA suggesting that such changes could be diagnostic for inhibition of CPT 1. Insulin and DC A (3mM) increased both malonyl-CoA and long chain fatty acyl-CoA content and decreased the ratio of fatty acylcarnitine/acyl-CoA and β-oxidation. Isoprenaline and palmitate (0.5mM) opposed the effects of insulin, by decreasing the contents of malonyl-CoA and long chain fatty acyl-CoA, increasing the ratio of fatty acylcarnitine/ acyl-CoA and increasing β-oxidation. These findings are consistent with the notion that all these agents can cause acute regulation of CPT 1 in type I skeletal muscle. In the presence of 5-amino-4-imidazolecarboxamide ribonucloeside (AICAR) (1mM) the malonyl-CoA content decreased by 65% and decreased the content of both long chain esters significantly, in particular long chain acyl-CoA. Oxidation of 14C-labelled exogenous and endogenous fatty acid was measured in soleus muscle strips incubated with insulin as mentioned above. Isoprenaline (10-7M) increased both processes (28% and 103% respectively). Indicating that isoprenaline has a lipolytic effect. AICAR (1mM) increased oxidation of exogenous fatty acid by 102% but had no effect on endogenous oxidation. It is therefore concluded that AICAR causes a decrease in lipolysis in muscle. Similar experiments led to the suggestion that dichloroacetate (3mM) had a lipolytic effect in muscle.

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