Fig. 8: Defective fatty acid utilization and lipid metabolism in Chkb−/− hindlimb muscle.
In muscles from Chkb+/+ mice there is a balance between storage of fatty acid as triacylglycerol (TG) and usage of fatty acids either as an energy source by mitochondria β-oxidation or membrane phospholipid synthesis. In hindlimb muscles from Chkb−/− mice, an inability to consume DG for PC synthesis results in an imbalance between storage and usage of fatty acids. Although the cells are able to increase PC uptake from plasma to compensate for defective PC synthesis, this genetic defect in PC synthesis drives large fluctuations in lipid metabolism. At an early stage of Chkb mediated muscular dystrophy (Phase 1), there is a 12- to 15-fold increase in the levels of the mitochondrial specific lipids CL and AcCa; the large increase in CL reflects the increase in mitochondrial size at this stage of the disease. The increase in AcCa level is likely due to the inability to consume DG for PC synthesis, resulting in an accumulation of its precursor-fatty acid which the cell attempts to consume via mitochondria β-oxidation, however there is a concomitant decrease in Ppar mediated expression of genes required for fatty acid conversion to AcCa for its import into mitochondria and consumption by β-oxidation. As the disease progresses (Phase 2), CL level returns to wild type (probably as a result of damaged mitochondrial inner membrane), and a 12-fold increase in the storage lipid TG occurs due to an inability consume AcCa and the shunting of fatty acids into storage lipid droplets.
