Abstract
There is no consensus for diagnosis or treatment of RA muscle loss. We aimed to investigate metabolites in arthritic mice urine as biomarkers of muscle loss. DBA1/J mice comprised collagen-induced arthritis (CIA) and control (CO) groups. Urine samples were collected at 0, 18, 35, 45, 55, and 65 days of disease and subjected to nuclear magnetic resonance spectroscopy. Metabolites were identified using Chenomx and Birmingham Metabolite libraries. The statistical model used principal component analysis, partial least-squares discriminant analysis, and partial least-squares regression analysis. Linear regression and Fisher’s exact test via the MetaboAnalyst website were performed (VIP-score). Nearly 100 identified metabolites had CIA vs. CO and disease time-dependent differences (p < 0.05). Twenty-eight metabolites were muscle-associated: carnosine (VIPs 2.8 × 102) and succinyl acetone (VIPs 1.0 × 10) showed high importance in CIA vs. CO models at day 65; CIA pair analysis showed histidine (VIPs 1.2 × 102) days 55 vs. 65, histamine (VIPs 1.1 × 102) days 55 vs. 65, and L-methionine (VIPs 1.1 × 102) days 0 vs. 18. Carnosine was fatigue- (0.039) related, creatine was food intake- (−0.177) and body weight- (−0.039) related, and both metabolites were clinical score- (0.093; 0.050) and paw edema- (0.125; 0.026) related. Therefore, muscle metabolic alterations were detected in arthritic mice urine, enabling further validation in RA patient’s urine, targeting prognosis, diagnosis, and monitoring of RA-mediated muscle loss.
Highlights
The normalized weights for visceral and brown fat were reduced in collageninduced arthritis (CIA) animals (54% and 39%, respectively) and ankle joint normalized weights and spleen normalized weights were increased in the CIA group when compared to CO (18% and 40%, respectively)
The dissected tibialis anterior and gastrocnemius muscles weighed less in the CIA than in the CO group (25% and 24%, respectively) and sarcoplasmic ratios were smaller in CIA when compared with CO (23% and 22% less sarcoplasmic ratio, respectively)
Several of the metabolites found in the urine of CIA mice with muscle loss were related to muscle metabolism
Summary
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by symmetric polyarthritis and systemic involvement [1]. It affects about 1% of people under 35 years old and more than 2% of adults over 60 years in the United States, and its prevalence has been reported worldwide [2]. While the joints are the main target of the disease, there are many extra-articular manifestations, such as body composition changes, which are strongly associated with long-term disability and premature mortality [3]. Significant loss of muscle mass is widely described in the literature as one of the major metabolism-related changes seen in RA [4]
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