Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle

Daniel R. Crooks, Thanemozhi G. Natarajan, Suh Young Jeong, Chuming Chen, Sun Young Park, Hongzhan Huang, Manik C. Ghosh, Wing Hang Tong, Ronald G. Haller, Cathy Wu, Tracey A. Rouault

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Iron-sulfur (Fe-S) clusters are ancient enzyme cofactors found in virtually all life forms. We evaluated the physiological effects of chronic Fe-S cluster deficiency in human skeletal muscle, a tissue that relies heavily on Fe-S cluster-mediated aerobic energy metabolism. Despite greatly decreased oxidative capacity, muscle tissuefrom patients deficient inthe Fe-S cluster scaffoldproteinISCUshowedapredominance of type I oxidative muscle fibers and higher capillary density, enhanced expression of transcriptional co-activator PGC-1α and increased mitochondrial fatty acid oxidation genes. These Fe-S cluster-deficient muscles showed a dramatic up-regulation of the ketogenic enzyme HMGCS2 and the secreted protein FGF21 (fibroblast growth factor 21). Enhanced muscle FGF21 expression was reflected by elevated circulating FGF21 levels in the patients, and robust FGF21 secretion could be recapitulated by respiratory chain inhibition in cultured myotubes. Our findings reveal that mitochondrial energy starvation elicits a coordinated response in Fe-S-deficient skeletal muscle that is reflected systemically by increased plasma FGF21 levels.

Original languageEnglish (US)
Article numberddt393
Pages (from-to)24-39
Number of pages16
JournalHuman molecular genetics
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle'. Together they form a unique fingerprint.

  • Cite this

    Crooks, D. R., Natarajan, T. G., Jeong, S. Y., Chen, C., Park, S. Y., Huang, H., Ghosh, M. C., Tong, W. H., Haller, R. G., Wu, C., & Rouault, T. A. (2014). Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. Human molecular genetics, 23(1), 24-39. [ddt393]. https://doi.org/10.1093/hmg/ddt393