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

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Abstract

The tissue-specific expressions of creatine kinase (CK) isoforms are regulated by the coordinated action of various transcription factors. The myogenic differentiation factor D (MyoD) family of proteins and the myocyte-specific enhancer binding factor 2 family of transcription factors are important in regulating the muscle-specific expression of cytosolic muscle-type CK (MCK) and mitochondrial CKs. As reported in some related studies, TNF-α mediated degradation of MyoD and myogenin mRNA may lead to severe muscle wasting and cachexia, which is characterized by a low transcript level of MCK and myosin heavy chain proteins. In our previous study, we reported on a complete loss of total CK activity and expression when sarcoma was induced in mouse skeletal muscle (Patra et al. FEBS J. 275 (2008) 3236–3247). This study aimed at investigating the transcriptional cascade of CK down-regulation in carcinogen-induced sarcoma in mouse muscle. Both CK deficiency and enhanced nitric oxide synthase (NOS) were known to augment mitochondrial biogenesis, so we also explored the activation of the transcriptional cascade of mitochondrial biogenesis in this cancer. We observed the activation of the TNF-α-mediated nitric oxide production pathway with NFκB activation and concomitant degradation of MyoD and myogenin mRNA. Exploration of mitochondrial biogenesis revealed high cytochrome c oxidase activity and mitochondrial DNA content in sarcoma. The PGC-related co-activator seems to have a major role in regulating mitochondrial biogenesis by upregulating nuclear respiratory factors and mitochondrial transcription factor A. From the above findings, it can be concluded that severe muscle degeneration leads to CK down-regulation in sarcoma, and that the stimulation of mitochondrial biogenesis indicated a scenario representing both CK deficiency and NOS overexpression on the one hand, and altered bioenergetic profiling on the other.

Abbreviations

CK:

creatine kinase

COX:

cytochrome c oxidase

CS:

citrate synthase

eNOS:

endothelial nitric oxide synthase

iNOS:

inducible nitric oxide synthase

MCK:

muscle-type CK

Mef2:

myocyte-specific enhancer binding factor 2

mtTFA:

mitochondrial transcription factor A

MyHC:

myosin heavy chain

MyoD:

myogenic differentiation factor D

NM:

normal muscle

NOS:

nitric oxide synthase

NRF:

nuclear respiratory factor

PGC:

peroxisome proliferator-activated receptor gamma co-activator

PRC:

PGC-related co-activator

sMitCK:

sarcomeric mitochondrial CK

ST:

sarcoma tissue

TNF-α:

tumor necrosis factor α

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Correspondence to Soumen Bera.

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Key words

  • Sarcoma
  • Creatine kinase
  • Nitric oxide synthase
  • Muscle degeneration
  • Mitochondrial biogenesis