Tour-de-Force

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007Studies have been conducted, revealing an increased level of PGC-1α during muscle regeneration, adynamic and complex event involving phagocytosis of muscle debris, revascularization, activation,proliferation and differentiation (Duguez et al., 2001). More specifically a study done by Duguez et al.,investigated and hypothesized that mitochondrial biogenesis would be stimulated during skeletal muscleregeneration through PGC-1α (Duguez et al., 2001).The study mentioned above focused on skeletal muscle and its capacity to regenerate after injury. Thestudy revealed that during muscle regeneration there was marked increase in mitochondrial respirationafter injection of bupivacaine (a chemical agent frequently used to study muscle regeneration due to itsstimulus for rapid muscle fiber necrosis (Duguez et al., 2001)). The research also visually examined themuscle regeneration process, by means of histochemical analysis of the tissues (Figure 3.2) Along sidethis the levels of mtTFA (mitochondrial transcription factor A) as well as PGC-1α mRNA levels wereassessed (Figure 3.3). At 10 days post bupivacaine injection there is a marked increase in the expressionof PGC-1α, consistent with the regeneration of muscle fibers and mtTFA observed in Figure 3.2c at 10days post bupivacaine injection. (Duguez et al., 2001)This indicates that PGC-1α is involved in the regeneration process of the muscle fibers in relation to anincreased rate of mitochondrial biogenesis.Figure 3.3:Effects of bupivacaine on mtTFA and PGC-1 mRNAlevel. During the time post-bupivacaine injection,increased levels of PGC-1α were as well asincreased levels of mtTFA.Source: Duguez et al., 2001Figure 3.2:Histochemical analysis of necrosis andmuscle regeneration. a) control tissue b) 3days post bupivacaine injection c)10 dayspost bupivacaine injection d) 35 days postbupivacaine injectionSource: Duguez et al., 2001It is relevant to investigate the functions of the PPAR family in terms of cell cycle proliferation as they havepalpable and important roles such as provoking mitochondrial biogenesis. Muscle fibers of adultorganisms are terminally differentiated and have lost the ability to proliferate. Nevertheless, they containan accumulation of satellite cells (myogenic stem cells) which are able to proliferate, inducing hypertrophyas well as muscle regeneration upon stimulations such as injury or increased physical activity (Li et. al.,2006). As is characteristic of cellular proliferation, increased ATP as well as mitochondrial biogenesis isrequired, processes which are under the control of the PPAR family proteins. Connections have beensuggested and PRC has been identified as having the characteristics of an immediate early gene (Duguezet. al. 2001; Melloul & Stoffel, 2004; Vercauteren et. al. 2006) nonetheless, there are no direct studieslinking the activation of all the PPAR family proteins directly to the cell cycle.p38 MAPK and PGC-1αResearches conducted in the field of the PPAR family have identified various upstream factors which areinvolved in the activation of these coactivators. Initially, researchers established that the posttranslationalcontrol of PGC-1α was conducted via a negative regulatory region, located between amino acids 170 andSCI 332 Advanced Molecular Cell Biology Research Proposal 60