Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007PGC-1βPGC-1β has a lot of similarity in function and sequencing as its isoform PGC-1α. On a global scale, boththese coactivators also share a similar distribution in specific tissues, with peak expression in brown fatand heart and differently distributed mRNAs in brown adipose tissue, specifically following cold exposureduring brown fat cell differentiation (Lin et al., 2001). PGC-1β has been implied in various physiologicalfunctions such as control over hepatic lipid synthesis and production (Lin et al., 2005). There is alsoevidence from transgenic expression experiments that PGC-1β is involved in mitochondrial biogenesis inskeletal muscle.PGC-1β, PGC-1α & PRCWhat the three isoforms all have in common is their relation to mitochondria. They are also all able to bindto NRF-1 (Vercauteren et al., 2006). There have been studies conducted which demonstrate anintracellular redundancy between PGC-1β and PGC-1α. The overexpression of PGC-1β lead to anincrease of a minor subset of PGC-1α target genes, the majority being involved in mitochondrial oxidativemetabolism as well as other related functions, but not many others (Sonoda et al., 2007). Additionally, theother two PPAR family members are not able to fully compensate for the PGC-1α KO as a study by Wulfet al. demonstrated.MAPK ErkTwo main MAPK pathways, Erk and p38 (Yu et al., 2001; Boppart et al., 2000) were demonstrated to beactivated by various forms of muscle contraction (Widegren et al., 2000). This suggests that the pathwaysare involved in regulation of skeletal muscle genes that change expression rate as a response to exercise.The MAPK-Erk 1/2 signalling pathway was demonstrated in exercise adaptation (Murgia et al., 2000),where an increased fibre percentage occurred during injury repair in vivo when Erk 1/2 was activatedthrough transfectionexperiments.The expression of PGC-1α mRNA levels wasassessed in C2C12skeletal muscle cellsexposed to palmitateeither in the presence orin the absence of severalinhibitors to study thebiochemical pathwaysinvolved (Coll et al.,2006). This studyreported that exposure ofC2C12 skeletal musclecells to 0.75 mmol/lpalmitate reduced PGC-1α mRNA levels. Thisrepression was attributedto MAPK-Erk activationsuggesting that PGC-1αexpression was reducedthrough a mechanisminvolving MAPK-Erk.Figure 5Figure 3.5:Erk pathway indicating the activation of CREBSource: Cell Signaling Technology, Inc., 2007SCI 332 Advanced Molecular Cell Biology Research Proposal 62