Combined methotrexate and coenzyme Q10 therapy in adjuvant-induced arthritis evaluated using parameters of inflammation and oxidative stress

Rheumatoid arthritis is a common severe joint disease that affects all age groups, it is thus of great importance to develop new strategies for its treatment. The aim of the present study was to examine the combined effect of coenzyme Q10 (CoQ10) and methotrexate (MTX) on the progression of adjuvant-induced arthritis in rats. Adjuvant arthritis (AA) was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiments included healthy animals, arthritic animals not treated, arthritic animals treated with CoQ10, with methotrexate, and with a combination of CoQ10 and methotrexate. The two latter groups received a daily oral dose of 20 mg/kg b.w. of CoQ10, either alone or with methotrexate in an oral dose of 0.3 mg/kg b.w. twice a week. We found that CoQ10 potentiated both the antiarthritic (decrease of hind paw volume) and the antioxidant effect of methotrexate on the level of oxidation of proteins (suppression of protein carbonyl level in plasma) as well as lipoperoxidation (suppression of levels of HNE-adducts and MDA-adducts to plasma proteins). The same effect was observed for plasmatic levels of CoQ9 and IL-1α, and partially also for γ-glutamyltransferase activity assessed in joints and spleen. Moreover, the combination therapy improved the functionality of peripheral blood neutrophils in AA, with a balancing effect on the immunosuppression caused by MTX monotherapy. In summary, combined administration of CoQ10 and methotrexate suppressed arthritic progression in rats more effectively than did MTX alone. This finding may help improve treatment of rheumatoid arthritis

Caloric restriction induces energy-sparing alterations in skeletal muscle contraction, fiber composition and local thyroid hormone metabolism that persist during catch-up fat upon refeeding

Weight regain after caloric restriction results in accelerated fat storage in adipose tissue. This catch-up fat phenomenon is postulated to result partly from suppressed skeletal muscle thermogenesis, but the underlying mechanisms are elusive. We investigated whether the reduced rate of skeletal muscle contraction-relaxation cycle that occurs after caloric restriction persists during weight recovery and could contribute to catch-up fat. Using a rat model of semistarvation-refeeding, in which fat recovery is driven by suppressed thermogenesis, we show that contraction and relaxation of leg muscles are slower after both semistarvation and refeeding. These effects are associated with (i) higher expression of muscle deiodinase type 3 (DIO3) which inactivates tri-iodothyronine (T3), and lower expression of T3-activating enzyme, deiodinase type 2 (DIO2), (ii) slower net formation of T3 from its T4 precursor in muscles, and (iii) accumulation of slow fibers at the expense of fast fibers. These semistarvation-induced changes persisted during recovery and correlated with impaired expression of transcription factors involved in slow-twitch muscle development.We conclude that diminished muscle thermogenesis following caloric restriction results from reduced muscle T3 levels, alteration in muscle-specific transcription factors, and fast-to-slow fiber shift causing slower contractility. Energy-sparing effects persist during weight recovery and likely contribute to catch-up fat

Modulation of SERCA in the chronic phase of adjuvant arthritis as a possible adaptation mechanism of redox imbalance

Adjuvant arthritis (AA) is a condition that involves systemic oxidative stress. Unexpectedly, it was found that sarcoplasmic reticulum Ca2 +-ATPase (SERCA) activity was elevated in muscles of rats with AA compared to controls, suggesting possible conformational changes in the enzyme. There was no alteration in the nucleotide binding site but rather in the transmembrane domain according to the tryptophan polar/non-polar fluorescence ratio. Higher relative expression of SERCA, higher content of nitrotyrosine but no increase in phospholipid oxidation in AA SR was found. In vitro treatments of SR with HOCl showed that in AA animals SERCA activity was more susceptible to oxidative stress, but SR phospholipids were more resistant and SERCA could also be activated by phosphatidic acid. It was concluded that increased SERCA activity in AA was due to increased levels of SERCA protein and structural changes to the protein, probably induced by direct and specific oxidation involving reactive nitrogen species