Formoterol decreases muscle wasting as well as inflammation in the rat model of rheumatoid arthritis

Abstract

Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. β2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective β2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected daily with 50 μg/kg sc formoterol or saline for 12 days. Body weight change, food intake, and arthritis index were analyzed. After euthanasia, in the gastrocnemius mRNA was analyzed by PCR, and proteins were analyzed by Western blotting. Arthritis decreased gastrocnemius weight, cross-sectional area, and myofiber size, whereas formoterol increased those variables in both arthritic and control rats. Formoterol decreased the external signs of arthritis as well as NF-κB(p65) activation, TNFα, and COX-2 levels in the gastrocnemius of arthritic and control rats. Those effects of formoterol were associated with a decreased expression of myostatin, atrogin-1, and MuRF1 and in LC3b lipidation. Arthritis increased the expression of MyoD, myogenin, IGF-I, and IGFBP-3 and -5 in the gastrocnemius. In control and in arthritic rats, treatment with formoterol increased Akt phosphorylation and myogenin levels, whereas it decreased IGFBP-3 expression in the gastrocnemius. These data suggest that formoterol has an anti-inflammatory effect and decreases muscle wasting in arthritic rats through increasing Akt activity and myogenin and decreasing myostatin, the p-NF-κB(p65)/TNF pathway, and IGFBP-3.

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

“…have shown that treatment with a high dose of FOR (2000 μg kg −1 ) up‐regulated the protein content of LC3‐I and LC3‐II and the mRNA levels of Map1lc3b but did not change the protein content of autophagy protein markers like p62, concluding that ALS was unaffected by β 2 ‐agonist. Conversely, treatment with a low dose of FOR (50 μg kg −1 ) reduced LC3 lipidation in atrophic muscles from arthritic rats . Therefore, the FOR effects on ALS seem to vary accordingly to the doses.…”

“…β 2 ‐agonists have been suggested to act at this level by increasing Akt/FoxO3 phosphorylation in fed and fasted states. As a consequence, the expression of some FoxO target genes, such as the muscle‐specific Ub‐ligases Atrogin‐1 and Murf1 , is down‐regulated by β 2 ‐agonists especially in atrophic muscles . Recently, two novel Ub‐ligases, Smart and Musa1 , controlled by FoxO have been identified as the critical genes for muscle loss; however, no information is available about their regulation by adrenergic system.…”

“…Although the mTORC1 inhibitor rapamycin (RAPA) almost entirely prevented CB‐induced muscle hypertrophy, it is unclear whether this kinase serves as an enhancer of protein synthesis, an inhibitor of autophagy, or both. The interpretation of the effects of sympathomimetics on autophagy in skeletal muscle are confusing since both increased and decreased protein content of the autophagy marker LC3‐II have been reported.…”

“…As a consequence, the expression of some FoxO target genes, such as the muscle-specific Ub-ligases Atrogin-1 and Murf1, is down-regulated by β 2 -agonists especially in atrophic muscles. 19,21,22,33 Recently, two novel Ub-ligases, Smart and Musa1, controlled by FoxO have been identified as the critical genes for muscle loss 31,34,35 ; however, no information is available about their regulation by adrenergic system. Akt/mTORC1 signalling not only stimulates protein synthesis but also inhibits proteolysis by blocking autophagy, 36 the pathway that delivers intracellular substrates to lysosomes.…”

Adjuvant‐induced arthritis affects testes and ventral prostate of Wistar rats

“…The obtained results 40 days post‐AIA induction showed firstly a reduced body mass in the AIA animals studied, which corroborates previous reports (Gómez‐SanMiguel et al ., ; Alabarse et al ., ). AIA‐induced body mass reduction is due mainly to sarcopenia, a phenomenon also observed in the rheumatoid cachexia.…”