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Title: Anti-inflammatory effects of ω-3 fatty acids on murine skeletal muscle cell differentiation
Author: Magee, Peter
Awarding Body: University of Salford
Current Institution: University of Salford
Date of Award: 2011
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Eicosapentaenoic acid (ERA) is an w-3 polyunsaturated fatty acid (PUFA) with anti-inflammatory and anti-cachetic properties. These properties have not previously been investigated simultaneously with regards to skeletal muscle damage and regeneration and therefore the main aim of this work was to examine the possible protective effects of ERA during damage induced by the pro-inflammatory cytokines TNF-a and TWEAK . Using an established model of myoblast differentiation, skeletal muscle cell differentiation was shown to be morphologically impaired by TNF-a and TWEAK. Formation of myotubes was restricted as shown by reduced myoblast fusion indices (Ml) and myotube widths. These effects were associated with TNF-a induced apoptosis. Both cytokines caused increased expression of pro-inflammatory gene targets of NF-KB activity; TNF-a and IL- 6 and in parallel, TNF-a treatment increased NF-KB activity and inhibited expression and activation of PPARy. EPA prevented the TWEAK /TNF-mediated loss of expression MyHC expression (reduced to 5-30% Ml) and significantly increased myogenic fusion (p<0.05) and myotube diameter (p<0.05) indices back to control levels (Back to approx 70% Ml). ERA protective activity was associated with blocking cell death pathways as ERA completely attenuated TNF-mediated increases in caspase-8 activity (p<0.05) and cellular necrosis/apoptosis (p<0.05) back to their respective control levels. This led to investigation of the possible mechanisms of action for ERA using the TNF-a damage model. ERA blocked NFKB activation, downstream gene targets of NF-KB activity, IL-6 and TNF-a, and was associated with upregulation and activation of PPARv. Pre-treatment with a specific PPARy antagonist (GW9662) inhibited these actions of ERA, thus confirming that ERA activity was at least partially dependent on PPARy. This thesis has shown for the first time that PUFA such as ERA promote skeletal muscle differentiation in opposition to pathological levels of inflammatory cytokines. Thus, PUFAs such as ERA may represent a class of naturally occurring, low toxicity, PPAR ligands that could have clinical applications for treatment of inflammation-associated ongoing skeletal muscle damage in chronic disease states or ageing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available