The temporal relationship between cardiolipin biosynthesis and remodeling enzymes and cardiolipin content during unloading atrophy in mouse soleus

Abstract

Skeletal muscle is a heterogeneous tissue that consists of individual fibers that differ in contractile and metabolic properties. Skeletal muscle is also dynamic in its ability to adapt to external stimuli through changes in cell size, number, and/or fiber type composition, which are matched by mitochondrial content. Mitochondria are central to skeletal muscle adaptations and mitochondrial energetic function is highly dependent on the membrane phospholipid composition, specifically the mitochondrially exclusive cardiolipin (CL). CL biosynthesis results in nascent CL which must be remodeled by tafazzin (Taz) to form the predominant CL species in mammals, tetralinoleoyl cardiolipin (TLCL). Previous research has shown that CL content and 18:2n6 composition decreased and Taz protein content increased in tenotomy-induced atrophied mouse soleus, suggesting the upregulation of Taz may play a role in slowing this process. Thus, the purpose of this thesis was to examine the temporal relationship between enzymes of CL biosynthesis and remodelling and CL content during unload induced atrophy. Fourteen days post tenotomy resulted in reduced expression of phosphatidyl glycerol phosphate synthase (PGS1) and Taz protein, as well as a reduction in CL content. PGS1 appeared to be reduced prior to changes to CL content, while Taz was reduced following changes to CL content, suggesting that CL content is mainly dependant on PGS1, and the reduction in total CL may have reduced the need for Taz. This is the first study to show a temporal relationship between CL, CL biosynthesis and remodeling enzymes during muscle atrophy. Our identification of the CL biosynthesis proteins which are impacted during muscle atrophy resulting in reduced CL content, may pave the path for future treatment strategies to preserve the function of these enzymes during atrophy, and maintain CL content.