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

40 Citations (Scopus)

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 2014

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Sulfur
Skeletal Muscle
Iron
Enzymes
Muscles
Slow-Twitch Muscle Fibers
Coenzymes
Skeletal Muscle Fibers
Electron Transport
Starvation
Energy Metabolism
Up-Regulation
Fatty Acids
fibroblast growth factor 21
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Crooks, D. R., Natarajan, T. G., Jeong, S. Y., Chen, C., Park, S. Y., Huang, H., ... 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

Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. / Crooks, Daniel R.; Natarajan, Thanemozhi G.; Jeong, Suh Young; Chen, Chuming; Park, Sun Young; Huang, Hongzhan; Ghosh, Manik C.; Tong, Wing Hang; Haller, Ronald G.; Wu, Cathy; Rouault, Tracey A.

In: Human Molecular Genetics, Vol. 23, No. 1, ddt393, 01.2014, p. 24-39.

Research output: Contribution to journalArticle

Crooks, DR, Natarajan, TG, Jeong, SY, Chen, C, Park, SY, Huang, H, Ghosh, MC, Tong, WH, Haller, RG, Wu, C & Rouault, TA 2014, 'Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle', Human Molecular Genetics, vol. 23, no. 1, ddt393, pp. 24-39. https://doi.org/10.1093/hmg/ddt393
Crooks, Daniel R. ; Natarajan, Thanemozhi G. ; Jeong, Suh Young ; Chen, Chuming ; Park, Sun Young ; Huang, Hongzhan ; Ghosh, Manik C. ; Tong, Wing Hang ; Haller, Ronald G. ; Wu, Cathy ; Rouault, Tracey A. / Elevated FGF21 secretion, PGC-1α and ketogenic enzyme expression are hallmarks of iron-sulfur cluster depletion in human skeletal muscle. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 1. pp. 24-39.
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