Abstract
Previous studies have shown that raising cytosolic calcium in myotubes induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis. This finding suggests that the increases in cytosolic calcium in skeletal muscle during exercise may mediate the exercise-induced increase in mitochondria. The initial aim of this study was to determine whether raising calcium in skeletal muscle induces the same adaptations as in myotubes. We found that treatment of rat epitrochlearis muscles with a concentration of caffeine that raises cytosolic calcium to a concentration too low to cause contraction induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis. Our second aim was to elucidate the pathway by which calcium induces these adaptations. Raising cytosolic calcium has been shown to activate calcium/calmodulin-dependent protein kinase in muscle. In the present study raising cytosolic calcium resulted in increases in phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2, which were blocked by the calcium/calmodulin-dependent protein kinase inhibitor KN93 and by the p38 mitogen-activated protein kinase inhibitor SB202190. The increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis were also prevented by inhibiting p38 activation. We interpret these findings as evidence that p38 mitogen-activated protein kinase is downstream of calcium/calmodulin-dependent protein kinase in a signaling pathway by which increases in cytosolic calcium lead to increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha expression and mitochondrial biogenesis in muscle.
Highlights
The initial purpose of this study was to determine whether raising cytosolic Ca2ϩ in a more biologically relevant model, skeletal muscle, induces an increase in mitochondrial biogenesis similar to that found in myotubes
Both the activity and expression of PGC-1␣ appear to be regulated by p38 MAPK [7, 22,23,24], which is activated in muscle by contractile activity (24 –26) and in myotubes by raising cytosolic Ca2ϩ [27]. p38 activates the transcription factor activating transcription factor 2 (ATF-2), which binds to the cAMP-response element binding site on the PGC-1␣ promoter and induces PGC-1␣ transcription [24, 28]
Inhibition of p38 MAPK Prevents the Ca2ϩ Induced Increase in Mitochondrial Biogenesis—Both the activity [7, 22, 23] and expression [24] of PGC-1␣ are regulated by p38 mitogen-activated protein kinase, and p38 MAPK is activated in muscle by exercise and contractions [17, 24, 26] and by raising cytosolic Ca2ϩ in myotubes [27]
Summary
The initial purpose of this study was to determine whether raising cytosolic Ca2ϩ in a more biologically relevant model, skeletal muscle, induces an increase in mitochondrial biogenesis similar to that found in myotubes. After finding that raising cytosolic Ca2ϩ in our skeletal muscle preparation does result in increases in PGC-1␣ expression and mitochondrial biogenesis, we used this model to try to elucidate the pathway by which the Ca2ϩ-induced increases in PGC-1␣ and mitochondrial biogenesis are mediated. Both the activity and expression of PGC-1␣ appear to be regulated by p38 MAPK [7, 22,23,24], which is activated in muscle by contractile activity (24 –26) and in myotubes by raising cytosolic Ca2ϩ [27]. Calcium Increases in PGC-1␣ and Mitochondrial Biogenesis mitochondrial biogenesis in muscle by activating a pathway that leads from CAMK to p38 MAPK
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