Abstract
Flaxseed oil is rich in ɑ-linolenic acid (ALA), which is the metabolic precursor of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study investigated the effect of flaxseed oil supplementation on lipopolysaccharide (LPS)-induced muscle atrophy and carbohydrate oxidation impairment in a piglet model. Twenty-four weaned pigs were used in a 2 × 2 factorial experiment including dietary treatment (5% corn oil vs. 5% flaxseed oil) and LPS challenge (saline vs. LPS). On day 21 of treatment, the pigs were injected intraperitoneally with 100 μg/kg BW LPS, or sterile saline. At 4 h after injection, blood, gastrocnemius muscle and longissimus dorsi (LD) muscle were collected. Flaxseed oil supplementation increased ALA, EPA, total n-3 polyunsaturated fatty acids contents, protein/DNA ratio, and pyruvate dehydrogenase complex (PDC) quantity in muscles (p<0.05). In addition, flaxseed oil reduced mRNA expression of toll-like receptor (TLR) 4 and nucleotide-binding oligomerization domain protein (NOD) 2 and their downstream signaling molecules in muscles, and decreased plasma concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8, and mRNA expression of TNF-α, IL-1β and IL-6 (p<0.05). Moreover, flaxseed oil inclusion increased the ratios of phosphorylated Akt 1/ total Akt 1 and phosphorylated forkhead Box O (FOXO) 1/ total FOXO1, and reduced mRNA expression of FOXO1, muscle RING finger (MuRF) 1, and pyruvate dehydrogenase kinase (PDK) 4 in muscles (p<0.05). These results suggest that flaxseed oil might have a positive effect on alleviating muscle protein loss and carbohydrates oxidation impairment induced by LPS challenge through regulation of TLR4/NOD and Akt/FOXO signaling pathway.
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Key Points
Skeletal muscle is the most widely distributed tissue in the body, which is involved in many important biological functions. It is also an important site to regulate the whole body metabolism. However, pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 may cause muscle atrophy and metabolic disturbance, which is one of the prominent features during inflammation and infection, and characterized by muscle strength loss, protein degradation, and carbohydrate metabolism impairment. The objective was to investigate whether flaxseed oil had a protective effect on muscle atrophy and carbohydrates oxidation impairment caused by LPS challenge, and to elucidate its molecular mechanism(s) in the weaned piglet model. Flaxseed oil inclusion increased ALA, EPA and total n-3 PUFA contents in muscles. In this study, flaxseed oil supplementation could optimize this ratio compare to corn oil.
In this study, flaxseed oil inclusion increased IL-10 and CCL2 mRNA expression in muscles. These results indicated that flaxseed oil could attenuate inflammatory response through blocking the formation of LPS/LBP/CD14 complexes, inhibiting TLR4 and NOD signaling pathways, and simultaneously stimulating IL-10 and CCL2 mRNA expression, which further alleviate muscle atrophy and carbohydrate oxidation impairment induced by LPS challenge.
Pro-inflammatory cytokines can lead to muscle protein loss directly or via alterations of Akt / FOXO/ ubiquitin-proteasome pathway (UPP). Akt / FOXO is a common signaling pathway influencing muscle protein breakdown and synthesis during inflammation. Various pathological and physiological conditions can activate these two ubiquitin-ligase enzymes and stimulate muscle proteolysis. In this study, diet supplemented with fish oil decreased Forkhead Box O (FOXO) 1 mRNA abundance, and increased phosphorylation of Akt and FOXO1 in muscles. In line with these results, in this study, flaxseed oil inclusion decreased mRNA expression of FOXO1, MAFbx and MuRF1, and elevated the ratios of p-Akt1 / tAkt1 and p-FOXO1 / t-FOXO1 in muscles, indicating flaxseed oil could have a positive effect on alleviating muscle protein loss through regulating Akt / FOXO1 / UPP signaling pathway.
In summary, diet supplemented with flaxseed oil might have a positive effect on alleviating muscle protein loss and carbohydrates oxidation impairment. These beneficial effects of flaxseed oil on muscles might be associated with regulating TLR4 / NODs and Akt / FOXO signaling pathways.