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The transcriptional cascade associated with creatine kinase down-regulation and mitochondrial biogenesis in mice

Soumen Bera1, Manju Ray

  • 1Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700 032, India. bcsb@iacs.res.in

Cellular & Molecular Biology Letters
|April 4, 2009
PubMed

Insights

Muscle degeneration in sarcoma causes creatine kinase (CK) down-regulation. This study reveals TNF-alpha activation, nitric oxide production, and stimulated mitochondrial biogenesis, indicating altered cellular energy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Tissue-specific creatine kinase (CK) isoforms are regulated by transcription factors like MyoD and MEF2.
  • Tumor necrosis factor-alpha (TNF-alpha) can degrade MyoD and myogenin mRNA, leading to muscle wasting and reduced muscle-type CK (MCK) expression.
  • Previous studies showed a complete loss of CK activity in sarcoma-induced mouse skeletal muscle.

Purpose of the Study:

  • Investigate the transcriptional regulation of CK down-regulation in carcinogen-induced mouse muscle sarcoma.
  • Explore the activation of mitochondrial biogenesis in sarcoma, considering the link between CK deficiency, nitric oxide synthase (NOS) overexpression, and mitochondrial biogenesis.

Main Methods:

  • Induced sarcoma in mouse skeletal muscle.
  • Analyzed transcriptional changes related to CK expression and mitochondrial biogenesis.
  • Measured enzyme activities (e.g., cytochrome c oxidase) and molecular markers (e.g., DNA content, mRNA levels).

Main Results:

  • Observed activation of the TNF-alpha pathway, leading to nitric oxide production and NFkappaB activation.
  • Confirmed degradation of MyoD and myogenin mRNA.
  • Found increased cytochrome c oxidase activity and mitochondrial DNA content in sarcoma.
  • Identified a role for PGC-related co-activators in upregulating nuclear respiratory factors and mitochondrial transcription factor A, driving mitochondrial biogenesis.

Conclusions:

  • Severe muscle degeneration in sarcoma results in creatine kinase (CK) down-regulation.
  • Stimulated mitochondrial biogenesis occurs alongside CK deficiency and NOS overexpression.
  • The findings suggest an altered bioenergetic profile in sarcoma-affected muscle tissue.

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