Sustained loss of Pptc7 triggers variable skeletal muscle dysfunction and diminished body mass through dysregulation of BNIP3

Abstract

The mitochondrial phosphatase PPTC7 is required to sustain mammalian metabolism, as its global knockout (KO) triggers hypoketotic hypoglycemia and perinatal lethality in mice. However, the extent to which the loss of Pptc7 manifests pathology beyond the perinatal transition is unknown. Furthermore, PPTC7 was recently identified as dual functional, regulating mitochondrial protein phosphorylation and receptor mediated mitophagy, rendering it unclear which function(s) may influence in vivo physiology. Here, we find that sustained, inducible Pptc7 KO decreased lean mass, compromised whole body oxygen consumption, and altered circulating metabolites in adult male mice. We hypothesized that these phenotypes stemmed from skeletal muscle dysfunction and found lower mass and fiber cross-sectional area with shifts in fiber type distribution in select muscles of the hindlimb in Pptc7 KO animals. Loss of PPTC7 increased BNIP3 protein levels and decreased mitochondrial content in skeletal muscle, suggesting elevated mitophagy may drive pathology. Consistently, KO of Bnip3 rescued the lower body weight and lean mass seen in inducible Pptc7 KO adult animals and partially rescued perinatal lethality in global Pptc7 KO mice. These data demonstrate that loss of PPTC7 incites surprisingly variable dysfunction across physiological contexts that at least partially stems from dysregulated BNIP3.