Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading

Raid Nisr, Dinesh Shah, Ian Ganley, Hari Hundal (Lead / Corresponding author)

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14 Citations (Scopus)
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Abstract

Sustained nutrient (fuel) excess, as occurs during obesity and diabetes, has been linked to increased inflammation, impaired mitochondrial homeostasis, lipotoxicity, and insulin resistance in skeletal muscle. Precisely how mitochondrial dysfunction is initiated and whether it contributes to insulin resistance in this tissue remains a poorly resolved issue. Herein, we examine the contribution that an increase in proinflammatory NFkB signalling makes towards regulation of mitochondrial bioenergetics, morphology, and dynamics and its impact upon insulin action in skeletal muscle cells subject to chronic fuel (glucose and palmitate) overloading. We show sustained nutrient excess of L6 myotubes promotes activation of the IKKβ-NFkB pathway (as judged by a six-fold increase in IL-6 mRNA expression; an NFkB target gene) and that this was associated with a marked reduction in mitochondrial respiratory capacity (>50%), a three-fold increase in mitochondrial fragmentation and 2.5-fold increase in mitophagy. Under these circumstances, we also noted a reduction in the mRNA and protein abundance of PGC1α and that of key mitochondrial components (SDHA, ANT-1, UCP3, and MFN2) as well as an increase in cellular ROS and impaired insulin action in myotubes. Strikingly, pharmacological or genetic repression of NFkB activity ameliorated disturbances in mitochondrial respiratory function/morphology, attenuated loss of SDHA, ANT-1, UCP3, and MFN2 and mitigated the increase in ROS and the associated reduction in myotube insulin sensitivity. Our findings indicate that sustained oversupply of metabolic fuel to skeletal muscle cells induces heightened NFkB signalling and that this serves as a critical driver for disturbances in mitochondrial function and morphology, redox status, and insulin signalling.

Original languageEnglish
Pages (from-to)4887-4904
Number of pages18
JournalCellular and Molecular Life Sciences
Volume76
Issue number24
Early online date17 May 2019
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Glucose
  • Insulin
  • Metabolism
  • Mitochondria
  • Muscle
  • NFkB
  • Palmitate
  • Respiration
  • Mitochondria, Muscle/genetics
  • Diabetes Mellitus/genetics
  • Humans
  • Signal Transduction/genetics
  • Energy Metabolism/genetics
  • Muscle, Skeletal/metabolism
  • Mitophagy/genetics
  • Insulin Resistance/genetics
  • Obesity/genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
  • Insulin/metabolism
  • Nutrients/metabolism
  • Inflammation/genetics
  • Glucose/metabolism
  • Muscle Fibers, Skeletal/metabolism
  • NF-kappa B/genetics

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