Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes

James A. Timmons, Jessica Norrbom, Camilla Schéele, Håkan Thonberg, Claes Wahlestedt, Per Tesch

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Physical activity enhances muscle mitochondrial gene expression, while inactivity and mitochondrial dysfunction are both risk factors for developing diabetes. Defective activation of the transcriptional coactivator PGC-1α may contribute to the gene expression pattern observed in diabetic and insulin-resistant skeletal muscle. We proposed that greater insight into the mitochondrial component of skeletal muscle "diabetes" would be possible if the clinical transcriptome data were contrasted with local muscle inactivity-induced modulation of mitochondrial genes in otherwise healthy subjects. We studied PPARGC1A (PGC-1α), PPARGC1B (PGC-1β), NRF1, and a variety of mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes critical for oxidative phosphorylation in soleus muscle biopsies obtained from six healthy men and women before and after 5 weeks of local muscle inactivity. Muscle inactivity resulted in a coordinated down-regulation of PGC-1α and genes involved with mitochondrial metabolism, including muscle substrate delivery genes. Decreased expression of the mtDNA helicase Twinkle was related to the decline in mitochondrial RNA polymerase (r=0.83, p<0.04), suggesting that mtDNA transcription and replication are coregulated in human muscle tissue. In contrast to the situation in diabetes, PGC-1β expression was not significantly altered, while NRF1 expression was actually up-regulated following muscle inactivity. We can conclude that reduced PGC-1α expression described in Type 2 diabetes may be partly explained by muscle inactivity. Further, although diabetes patients are typically inactive, our analysis indicates that local muscle inactivity may not be expected to contribute to the decreased NRF1 and PGC-1β expression noted in insulin-resistant and Type 2 diabetes patients, suggesting these changes may be more disease specific.

Original languageEnglish (US)
Pages (from-to)165-172
Number of pages8
JournalGenomics
Volume87
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Keywords

  • Diabetes transcriptome
  • Disease mechanisms
  • Human skeletal muscle
  • Mitochondria
  • MTERF
  • NRF1
  • Physical activity
  • PPARGC1A
  • PPARGC1B
  • TFAM
  • TFB1M
  • TFB2M

ASJC Scopus subject areas

  • Genetics

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