The effects of chronic muscle use and disuse on cardiolipin metabolism

Abstract

Cardiolipin (CL) is a phospholipid that maintains the integrity of mitochondrial membranes. We previously demonstrated that CL content increases with chronic muscle use, and decreases with denervation-induced disuse. To investigate the underlying mechanisms, we measured the mRNA expression of 1) CL synthesis enzymes cardiolipin synthase (CLS) and CTP:PA-cytidylyltransferase-1 (CDS-1); 2) remodeling enzymes tafazzin and acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1); and 3) outer membrane CL enzymes, mitochondrial phospholipase D and phospholipid scramblase 3 (Plscr3), during chronic contractile activity (CCA)-induced mitochondrial biogenesis and denervation. With CCA, CDS-1 expression increased by 128%, parelleling CL levels. Surprisingly, denervation also led to large increases in CDS-1 and CLS, despite a decrease in mitochondria, possibly due to a compensatory mechanism to restore lost CL. ALCAT1 decreased by 32% with CCA, but increased by 290% following denervation, indicating that both CCA and denervation alter CL remodeling. CCA and denervation also elicited 60-90% increases in Plscr3, likely to facilitate CL movement to the outer membrane. The expression of these genes was not affected by aging, but changes due to CCA and denervation were attenuated compared with young animals. The absence of PPARγ coactivator-1α in knockout animals led to a decrease in CDS-1 and an increase in ALCAT1 mRNA levels, implicating PGC-1α in regulating both CL synthesis and remodeling. These data suggest that chronic muscle use and disuse modify the expression of mRNAs encoding CL metabolism enzymes. Our data also illustrate, for the first time, that PPARγ coactivator-1α regulates the CL metabolism pathway in muscle.

Cardiolipin content, linoleic acid composition, and tafazzin expression in response to skeletal muscle overload and unload stimuli

“…To our knowledge, this is the first study to demonstrate muscle type differences in Taz protein. Overall, our results are partly consistent with a previous study whereby chronic muscle use led to increases in CL content; however, CL 18:2 n 6 composition was not examined 29 . Furthermore, in the study by Ostojic et al ., chronic contractile activity did not lead to any changes in Taz expression, however, only mRNA levels were examined, and the fact that mRNA and protein content are not directly proportional is generally well accepted.…”

“…Although purely speculative, we view that this increase in Taz protein may be an adaptive response that acts to combat the reductions in mitochondrial CL content and CL 18:2 n 6 composition. Altogether, these findings in the unloaded soleus are partly consistent with a previous study whereby muscle disuse led to a decrease in CL content; however, CL 18:2 n 6 composition was not examined 29 . Furthermore, in the study by Ostojic et al ., muscle disuse via denervation did not lead to any changes in tafazzin expression, however, only mRNA levels were examined.…”

Looking Beyond Structure: Membrane Phospholipids of Skeletal Muscle Mitochondria

“…Exercise training increases abundance of enzymes of CL and PI synthesis [47, 68]. It is not clear how exercise training increases synthesis/import of other mitochondrial phospholipids, but such a mechanism(s) likely involves an action of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α).…”

“…Skeletal muscle-specific overexpression of PGC1α is sufficient to increase PC and PE, while its absence results in ablation of exercise-induced increases in cellular PC and PE [63, 69]. PGC1α may also play a role in CL synthesis [68], though Akt and AMP-activated protein kinase (AMPK) are also likely involved [47, 70]. …”

New targets for monitoring and therapy in Barth syndrome

“…However, chronic use and disuse of muscles in a rat model was shown to affect expression of cardiolipin synthetic enzymes. 43 More research is warranted to determine whether cardiolipin abnormalities are a mechanism of skeletal dysfunction in other conditions, although this seems to be a plausible hypothesis.…”