Mitochondrial activity is a major regulator of myoblast differentiation and of the expression of myosin isoforms

Abstract

Besides their influence on fuel metabolism, mitochondrial activity is also involved in the induction of apoptosis and in the regulation of cell proliferation and differentiation. In particular, an actual regulation of myoblast differentiation by mitochondrial activity is well esta-blished, independently of ATP synthesis, through the control of myogenin expression and myogenic factor activity.

In this study, we established that c-Myc expression is respectively up- or down-regulated by inhibition or stimulation of mitochondrial activity. This regulation essentially takes place at a post-transcriptional level and also concerns, in avian myoblast, the cellular localisation of the protein. In addition, c-Myc overexpression exactly mimics the influence of an inhibition of mitochondrial activity : i) inhibition of myoblast differentiation ; ii) inhibition of myogenin expression ; iii) inhibition of myogenic factor ability to induce differentiation ; iv) inhibition of myoblast withdrawal from the cell cycle. These results demonstrate that c-Myc is an important target of mitochondrial activity involved in the myogenic influence of the organelle.

We also identified another target gene of mitochondrial activity encoding the calcium-dependent phosphatase calcineurin. Its expression is respectively inhibited or stimulated by inhibition or stimulation of mitochondrial activity. In addition, expression of a constitutively active form of calcineurin stimulates of myoblast differentiation and myosin isoform expression, whereas these two events are suppressed by expression of antisense calcineurin RNA. Lastly, stimulation of mitochondrial activity or overexpression of the constitutively active form of calcineurin specifically stimulates the expression of slow myosin heavy chain isoform.

These data demonstrate that, partly via calcineurin expression, mitochondrial activity not only regulates myoblast differentiation, but also the contractile type of muscle fibres.