Cyclophilin‐D is dispensable for mitochondrial apoptotic signaling through opening of the permeability transition pore in denervated muscle

Abstract

We specifically determined whether the regulating protein cyclophilin-D (CypD), through opening of the permeability transition pore (PTP), is involved in the activation of mitochondria-derived apoptotic signaling previously described in skeletal muscle following loss of innervation. CypD-defficient mice (CypD-KO) and their littermate controls were submitted to unilateral sciatic nerve transection. Mitochondrial resistance to Ca2+-induced opening of the PTP, and muscle apoptotic signaling were investigated 14 days post-surgery. At the whole muscle level, lack of CypD, despite conferring greater resistance to PTP opening, did not protect against atrophy, release of mitochondrial pro-apoptotic factors and activation of caspases following denervation. Denervation in CypD-KO mice still resulted in a facilitation of PTP opening compared to normally innervated contralateral muscle. This indicates that CypD-independent factors could poise mitochondria from denervated muscle toward PTP opening in vitro. All together, these results provide direct evidence that Cyp-D-dependent PTP opening is dispensable for apoptotic signaling in skeletal muscle following denervation.