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

The
switch from glycolytic to oxidative muscle fiber types is one adaption in
skeletal muscle during endurance exercise that is correlated with favorable whole
body metabolic improvements that counteract obesity and obesity-related
diseases. Although the precise mechanisms and biological functions are unknown,
increased DHA incorporation into the membrane phospholipids PC and PE also
occurs during this adaptation and correlates with enhanced oxidative fiber
content and oxidative metabolic capacity. Also, the molecular mechanisms of increased
phospholipid-DHA levels in endurance-trained muscle are unclear. The nuclear receptor coactivator PGC1a is
activated to mediate mitochondrial biogenesis and increase oxidative capacity
in skeletal muscle during exercise. Senoo et al. (2015) showed
that PGC1a
overexpression resulted in altered phospholipid profiles in skeletal muscle,
with the biggest increase in PC and PE in glycolytic EDL muscles. These changes
also occurred after exercise in a PGC1a-dependent mechanism, whereas oxidative soleus muscle had
relatively high phospholipid-DHA content even without training. Their study indicated
that higher DHA-content of these trained muscle may be mediated by
endurance-exercise-activated cellular pathways. The lab identified LPAAT3,
which is an enzyme that is up-regulated during in vitro myoblast
differentiation that promoted DHA incorporation into PC and PE. LPAAT3
expression increased by pharmacological activators of PPARd and AMPK. PGC1a is activated downstream of AMPK and is a
coactivator of PPARd (Kleiner
et al., 2009), thus increased LPAAT3 expression could be a common mechanism to
increase DHA incorporation into PC and PE through overlapping PPARd and AMPK/PGC1a pathways.

            DHA
is widely used as a dietary supplement for its various metabolic health
benefits. However, the effects of DHA incorporation into muscle phospholipids during
exercise are not well understood, as it could have an impact on cell metabolism
by different several mechanisms. Due to its high unsaturation level (number of
double bonds), increased DHA is thought to increase curvature and fluidity of
cell membranes, which could affect cell organelle functions. One study showed
that a twelve-week fish oil supplementation given to active men resulted in increased
DHA incorporation and eicosapentaenoic acid (EPA) into PC and PE of skeletal
muscle mitochondrial membranes, accompanied by improvements in mitochondrial
respiratory function (Herbst et al. J Physiol.
2014). However, the cause of these improvements is unclear, whether was
due to biophysical changes in the mitochondrial membranes or other mechanisms,
since the free fatty acid DHA or EPA levels could directly affect metabolic
gene expression by activating lipid-sensing transcription factors such as PPARs
and other molecules. Because skeletal muscle DHA levels may affect metabolism by various mechanisms, in order to
study the physiological consequences, it is important to first identify the
mechanisms that govern partitioning of DHA between phospholipid and free fatty acid form. We
will explore whether LPAAT3 levels is differentially regulated in skeletal muscle
depending on the transcriptional activities of PPARd and AMPK/PGC1a, to thereby regulate phospholipid-DHA
levels with possible effects related
to metabolic gene transcription or membrane properties. Identification of the mechanisms that
regulate DHA content into the cell membrane will broaden our understanding of
metabolic effects of DHA and related health benefits associated with fish oil
and exercise.

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