Mitochondrial permeability transition in skeletal muscle phenocopies muscle alterations seen in cancer cachexia and other wasting conditions.

Skeletal muscle in wasting conditions often exhibits atrophy, mitochondrial respiratory dysfunction and fragmentation of the acetylcholine receptor (AChR) cluster at the endplate. The accompanying alterations in mitochondrial morphology suggest that mitochondria may be involved in muscle pathology in these conditions. To address this gap, we tested an established pathological mechanism in ischaemia-reperfusion injury and neurodegeneration but poorly studied in skeletal muscle: mitochondrial permeability transition (mPT). We tested if mPT recapitulated phenotypes common in wasting conditions, whether tumour-conditioned media (TCM) could promote mPT and compared differentially expressed genes (DEGs) induced by mPT with DEGs observed in a mouse model of pancreatic cancer cachexia. Inducing mPT in mouse skeletal muscle bundles progressively altered mitochondrial cristae morphology, culminating in a breach of the outer mitochondrial membrane. Inducing mPT in mouse muscle fibres increased mitochondrial reactive oxygen species (mROS) and caspase 3 activity and caused atrophy. Inducing mPT caused a complex I mitochondrial respiratory impairment, increased lysosome-mitochondrion colocalization and fragmented the AChR cluster at the muscle endplate. The Ca2+ threshold for mPT, mitochondrial calcein colocalization and mitochondrial membrane potential were reduced by TCM in skeletal muscle or C2C12 myoblasts, respectively. Knockout of the mPT-regulating protein CypD attenuated the reduction in Ca2+ threshold for mPT by TCM. Inhibitors of mPT attenuated atrophy with TCM in C2C12 and human primary myotubes. Finally, there was overlap between the DEGs of mPT and diaphragm muscle in a mouse model of pancreatic cancer cachexia during the muscle-wasting phase. We conclude that mPT should be explored as a therapeutic target in muscle-wasting disorders. KEY POINTS: Mitochondrial permeability transition (mPT) induces marked alterations in mitochondrial morphology and muscle phenotypes that are common in wasting conditions. mPT is promoted by tumour-derived factors in a manner that depends in part on the mPT-regulating protein CypD. mPT generates transcriptional alterations that overlap with cachectic muscle in a mouse model of pancreatic cancer, particularly during the period of muscle wasting. Pharmacological targeting of mPT attenuates or prevents atrophy in C2C12 and human primary myotubes, respectively.