Mitochondria are highly dynamic organelles that continuously and reversibly rearrange their structure through the tightly-regulated processes of fission and fusion of their inner and outer membranes. During myogenic differentiation short mitochondria of myoblasts change into an elongated network observed in myotubes. Mitochondrial elongation is required for myogenesis to occur and this event depends on cellular generation of nitric oxide (NO). When NO pathway is blocked, mitochondria fragment and display a latent dysfunction. Despite the apoptotic behaviours of mitochondria, myoblasts don’t undergo apoptosis. Recently it has been demonstrated that, in skeletal muscle dysfunctional mitochondria are degraded by an autophagic process, called mitophagy, mediated by the AKT/FoxO3 pathway. Here, we investigate the induction of mitophagy during muscle differentiation and its role in preventing apoptosis. We observe mitochondrial fission in the presence of inhibitors of NO pathway and this accounts for inhibition of the myogenic programme of myoblasts. Fragmentation causes a latent mitochondrial dysfunction and reduces ATP production. Despite these apoptotic features, cells don’t undergo apoptosis and only in presence of 3MA that blocks lysosomal degradation we can detect annexin V positive cells. Dysfunctional mitochondria are degraded by the activation of autophagy; in this condition the phosphorylation levels of Akt and FoxO3 are reduced, as a clear sign of mitophagy induction. These results demostrate the involment of FoxO3 pathway on autophagy regulation. We observed the same results also on nNOS-KO in vivo model that show fragmented mitochondria, reduction of myogenic differentiation and increase of autophagy.
OSSIDO NITRICO E MITOCONDRI: NUOVE REGOLAZIONI E FUNZIONI NELLA FISIOLOGIA DEL MUSCOLO SCHELETRICO / S. Pisoni ; tutor: E. Clementi ; correlatore: C. De Palma ; coordinatore: A. Panerai. Universita' degli Studi di Milano, 2012 Feb 03. 24. ciclo, Anno Accademico 2011.
OSSIDO NITRICO E MITOCONDRI: NUOVE REGOLAZIONI E FUNZIONI NELLA FISIOLOGIA DEL MUSCOLO SCHELETRICO
S. Pisoni
2012
Abstract
Mitochondria are highly dynamic organelles that continuously and reversibly rearrange their structure through the tightly-regulated processes of fission and fusion of their inner and outer membranes. During myogenic differentiation short mitochondria of myoblasts change into an elongated network observed in myotubes. Mitochondrial elongation is required for myogenesis to occur and this event depends on cellular generation of nitric oxide (NO). When NO pathway is blocked, mitochondria fragment and display a latent dysfunction. Despite the apoptotic behaviours of mitochondria, myoblasts don’t undergo apoptosis. Recently it has been demonstrated that, in skeletal muscle dysfunctional mitochondria are degraded by an autophagic process, called mitophagy, mediated by the AKT/FoxO3 pathway. Here, we investigate the induction of mitophagy during muscle differentiation and its role in preventing apoptosis. We observe mitochondrial fission in the presence of inhibitors of NO pathway and this accounts for inhibition of the myogenic programme of myoblasts. Fragmentation causes a latent mitochondrial dysfunction and reduces ATP production. Despite these apoptotic features, cells don’t undergo apoptosis and only in presence of 3MA that blocks lysosomal degradation we can detect annexin V positive cells. Dysfunctional mitochondria are degraded by the activation of autophagy; in this condition the phosphorylation levels of Akt and FoxO3 are reduced, as a clear sign of mitophagy induction. These results demostrate the involment of FoxO3 pathway on autophagy regulation. We observed the same results also on nNOS-KO in vivo model that show fragmented mitochondria, reduction of myogenic differentiation and increase of autophagy.File | Dimensione | Formato | |
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