Protective Effects And Mechanistic Studies Of Pyrroloquinoline Quinone On Exercise-Induced Fatigue

Background:Fatigue has a significant impact on exercise outcome,and affects human health,work and life.Thus,it draws a lot of interest to explore new anti-fatigue nutritional factors and develop safe and efficient anti-fatigue functional supplements for improving exercise ability and promoting human health.Pyrroloquinoline quinone(PQQ)has a variety of biological functions,such as anti-oxidation,anti-inflammatory,and maintaining normal mitochondrial function,suggesting that it may have important research and development value in anti-fatigue injury induced by over-exercise,but so far,no relevant research has been reported.Objective:The present study assessed the potential protective effects and mechanism of PQQ against the fatigue,oxidative stress,tissue injury,inflammation and apoptosis caused by over-exercise.The study will provide a theoretical support for the development of PQQ as an efficient supplement in anti-fatigue injury induced by over-exercise.Design:1.Cell and animal models for over exercise-induced fatigue were established,and the parameters including TTE(the time to exhaustion),ROS(reactive oxygen species),CK(creatine kinase),LDH(lactate dehydrogenase),cTnI(cardiac troponin I),SOD(superoxide dismutase),GSH-Px(glutathione peroxidase)activity levels,and the expression of NF-?B(nuclear factor kappa B),IL-6(interleukin-6),IL-1?(interleukin1?),CXCL10(interferon-inducible protein-10),Bcl-2(B-cell lymphoma-2),Bax(Bcl-2associated X protein)and Caspase-3 were measured to evaluate the function of PQQ in the models.2.The mitochondrial function was studied by testing changes on mitochondrial morphology,membrane potential,mitochondrial respiratory function,and adenosine triphosphate(ATP)levels.Moreover,mitochondrial complex I inhibitor was used to identify its possible targets.3.The overall changes of serum metabolic profiles were analyzed by GC-MS metabolomics.Furthermore,principal component analysis(PCA)and orthogonal partial least square-iscriminate analysis(OPLS-DA)were used to identify key potential markers,elaborate the metabolic pathways and regulatory mechanisms of PQQ,and explore its possible targets.Result:1.PQQ was able to inhibit the production of ROS,the LDH activity of the medium,the over-expression of transcription factor NF-kappa B,as well as to decrease m RNA expression of IL-6,IL-1?,interferon-inducible protein-10(CXCL10)and Caspase-3 in the cell model of exercise-induced fatigue.2.PQQ was able to prolong the time of exhaustive exercise,decrease the activity of CK,LDH and cTnI in the serum,increase the activity of SOD and GSH-Px in the heart and liver,reduce the expression and release of inflammatory mediators such as TNF-a,IL-1?,IL-6,CXCL-10,up-regulate the proportion of Bcl-2 and Bax,and inhibit the over-expression and activation of NF-?B(p65)and caspase-3.3.PQQ is able to maintain the normal morphology and function of mitochondria in over exercise-induced fatigue model.Moreover,mitochondrial complex I is likely a possible target of PQQ.4.Over exercise-induced fatigue could lead to metabolic disorders,and suggest that PQQ may play an important role in maintaining normal serum metabolic level.The levels of citric acid,L-proline,xylitol,N-acetyl-L-phenylalanine were changed,and their related metabolic pathways were affected.Conclusion:We first demonstrate that PQQ can delay over exercise-induced fatigue and improve exercise ability.Furthermore,in the cell and animal models for over exercise-induced fatigue,PQQ can significantly protect mice from the oxidation,inflammation,tissue damage and mitochondrial dysfunction and so on.The data suggest that PQQ may be used as a nutritional supplement to improve exercise outcome.