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

• DOI: 10.1007/s00018-019-03148-8
• Publication Date: 2019-05-17T16:34:48Z
• Authors: Raid B. Nisr; Dinesh S. Shah; Ian G. Ganley; Harinder S. Hundal
• Keywords: MFN2; UCP3; Proinflammatory cytokine; Mitochondrial ROS; Lipotoxicity

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