The metabolic improvements that counteract obesity and obesity-related diseases.

Theswitch from glycolytic to oxidative muscle fiber types is one adaption inskeletal muscle during endurance exercise that is correlated with favorable wholebody metabolic improvements that counteract obesity and obesity-relateddiseases.

Although the precise mechanisms and biological functions are unknown,increased DHA incorporation into the membrane phospholipids PC and PE alsooccurs during this adaptation and correlates with enhanced oxidative fibercontent and oxidative metabolic capacity. Also, the molecular mechanisms of increasedphospholipid-DHA levels in endurance-trained muscle are unclear. The nuclear receptor coactivator PGC1a isactivated to mediate mitochondrial biogenesis and increase oxidative capacityin skeletal muscle during exercise. Senoo et al. (2015) showedthat PGC1aoverexpression resulted in altered phospholipid profiles in skeletal muscle,with the biggest increase in PC and PE in glycolytic EDL muscles. These changesalso occurred after exercise in a PGC1a-dependent mechanism, whereas oxidative soleus muscle hadrelatively high phospholipid-DHA content even without training. Their study indicatedthat higher DHA-content of these trained muscle may be mediated byendurance-exercise-activated cellular pathways. The lab identified LPAAT3,which is an enzyme that is up-regulated during in vitro myoblastdifferentiation that promoted DHA incorporation into PC and PE.

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LPAAT3expression increased by pharmacological activators of PPARd and AMPK. PGC1a is activated downstream of AMPK and is acoactivator of PPARd (Kleineret al., 2009), thus increased LPAAT3 expression could be a common mechanism toincrease DHA incorporation into PC and PE through overlapping PPARd and AMPK/PGC1a pathways.             DHAis widely used as a dietary supplement for its various metabolic healthbenefits. However, the effects of DHA incorporation into muscle phospholipids duringexercise are not well understood, as it could have an impact on cell metabolismby different several mechanisms. Due to its high unsaturation level (number ofdouble bonds), increased DHA is thought to increase curvature and fluidity ofcell membranes, which could affect cell organelle functions.

One study showedthat a twelve-week fish oil supplementation given to active men resulted in increasedDHA incorporation and eicosapentaenoic acid (EPA) into PC and PE of skeletalmuscle mitochondrial membranes, accompanied by improvements in mitochondrialrespiratory function (Herbst et al. J Physiol.2014). However, the cause of these improvements is unclear, whether wasdue to biophysical changes in the mitochondrial membranes or other mechanisms,since the free fatty acid DHA or EPA levels could directly affect metabolicgene expression by activating lipid-sensing transcription factors such as PPARsand other molecules. Because skeletal muscle DHA levels may affect metabolism by various mechanisms, in order tostudy the physiological consequences, it is important to first identify themechanisms that govern partitioning of DHA between phospholipid and free fatty acid form.

Wewill explore whether LPAAT3 levels is differentially regulated in skeletal muscledepending on the transcriptional activities of PPARd and AMPK/PGC1a, to thereby regulate phospholipid-DHAlevels with possible effects relatedto metabolic gene transcription or membrane properties. Identification of the mechanisms thatregulate DHA content into the cell membrane will broaden our understanding ofmetabolic effects of DHA and related health benefits associated with fish oiland exercise.