Figure 9

Proposed model whereby AngII infusion leads to mitochondrial dysfunction and skeletal muscle wasting. Parallel to the well-characterized AngII-mediated activation of the FOXO-E3-UPS axis via inhibition of Akt, AngII also induces expression of the phosphatase PP2Cα, which dephosphorylates and inactivates AMPK. This leads to reduced PGC-1α, NRF1, and TFAM expression (less mitochondrial biogenesis), and reduced ULK1 activity. The AngII-mediated reduction in ULK1 activation inhibits a critical early step in the autophagy pathway and prevents recycling of damaged mitochondria (mitophagy). AngII also inhibits both mitochondrial fission and fusion through predominately AMPK-independent pathways, which likely contribute to mitochondrial dysfunction caused by elevated AngII. Prolonged mitochondrial dysfunction and energy depletion ultimately leads to release of caspase-3, initiation of apoptosis, and wasting.