Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders

Mitochondrial disorders (MDs) are heterogeneous multisystemic disorders due to impaired oxidative phosphorylation causing defective mitochondrial energy production. Common histological hallmarks of MDs are ragged red fibers (RRFs), muscle fibers with abnormal focal accumulations of mitochondria. In contrast to the growing understanding of the genetic basis of MDs, the fate of phenotipically affected muscle fibers remains largely unknown. We investigated programmed cell death (PCD) in muscle of 17 patients with mitochondrial respiratory chain dysfunction. We documented that in affected muscle fibers, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1, caspase-9 that, in turn, activates effector caspase-3, -6, and -7, suggesting the execution of the intrinsic apoptotic pathway. While active caspase-3 underwent nuclear translocation, AIF mainly stayed within mitochondria, into which an upregulated Bax is relocated. The significant increase in caspase-2, -3 and -6 activity strongly suggest that cell death program is caspase-dependent and the activation of caspase-2 together with PUMA up-regulation point to a role of oxidative stress in triggering the intrinsic pathway. Concurrently, in muscle of patients the number of satellite cells was significantly increased and myonuclei were detected in different stages of myogenic differentiation indicating that a reparative program is ongoing in MDs muscles.Together these data suggest that in MDs patients affected muscle fibers are trapped in a mitochondria-regulated caspase-dependent PCD while repairing events simultaneously take place.