Regulation of mitochondrial function and protein homeostasis by hypoxia inducible factor 1 alpha in normoxia-mouse tissues

ABSTRACT: Hypoxia inducible factors (HIF), specifically, HIF1A, is continuously synthesized and degraded rapidly in normoxia. During hypoxia, HIF1A stabilization limits oxygen utilization and inhibits protein synthesis, but there are limited data on HIF1A function(s) in normoxia. Given the high energy needs of contraction and maintenance of the large protein mass in skeletal muscle, we determined HIF1A function in normoxia in differentiated murine myotubes with loss/gain of function and skeletal muscle from mice with Hif1afl/f or post-natal muscle-specific deletion (Hif1amsd). Integration of transcriptomics and proteomics in myotubes and muscle from mice with Hif1amsd showed enrichment of mitochondrial/metabolic regulatory molecules including TCA cycle and electron transport chain components. Mitochondrial oxidative functions and ATP content were higher with less free radical generation with Hif1a deletion. Untargeted metabolomics showed enrichment in TCA cycle components and senescence regulation. Targeted metabolomics showed higher concentrations of most TCA cycle intermediates and expression of sirtuin 3, with less abundance of markers of post-mitotic senescence. Under normoxia, regulation of mitochondrial oxidation and post-mitotic senescence in skeletal muscle by the transient expression of HIF1A may have relevance in other tissues also.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

DISEASE(S): Skeletal Muscle Atrophy

SUBMITTER: Ling Li  

LAB HEAD: Srinivasan Dasarathy

PROVIDER: PXD041880 | Pride | 2025-06-09

REPOSITORIES: Pride