Compensatory anabolic signaling in the sarcopenia of experimental chronic arthritis

Robert D Little,Amanda Villalvilla,Raquel Largo,Paula Gratal,Sandra Pérez-Baos,Iván Prieto-Potin,Gabriel Herrero-Beaumont,Flavia Cicuttini

doi:10.1038/s41598-017-06581-6

Abstract

Inflammatory activity in rheumatoid arthritis may alter the regulation of muscle mass leading to a secondary sarcopenia, commonly termed rheumatoid cachexia (RC). We characterized alterations to muscle structure and various pro-inflammatory, catabolic and regenerative markers in an animal model of RC. Antigen induced arthritis (AiA) was performed in 20 male adult rabbits. AiA animals exhibited significantly less weight gain, a markedly elevated serum C-reactive protein (CRP), lighter muscles with shorter cross-sectional diameter and increased myonuclei when compared to controls. Atrogin-1 and MuRF-1 were up-regulated alongside an increase in IL-1β, active NF-κB and a higher ratio of phosphorylated to inactive p38 MAPK. CCL-2 and TNF levels were reduced and IL-6 was unchanged between groups. We observed decreased pSTAT3, unchanged pSTAT1 and Myf5, but increased Pax7, MyoD and myogenin. AiA rabbits had a reduction in myostatin from gastrocnemii and synovium with a congruent decrease in serum myostatin compared to controls. Chronic arthritis induced an RC-like secondary sarcopenia with increased muscle protein breakdown. Elevated IL-1β may trigger proteolysis via elevated NF-κB and p38 MAPK signaling with a compensatory anabolic response suggested by myonuclear expansion, increased Pax7, MyoD and myogenin, reduced pSTAT3 as well as reduced serum, synovial and muscular myostatin.

Highlights

Primary sarcopenia is a phenomenon of age-related loss of muscle mass and function affecting up to 30% of older adults[1]
We have studied the histological alterations of muscle wasting in an animal model of chronic arthritis and the derangement of various markers of catabolism and regeneration
While Rheumatoid cachexia (RC) in humans is widely reported to be associated with stable weight or weight gain, our results are consistent with previous animal models of inflammatory arthritis in rabbits[33], rats[34], mice[35] and monkeys[36]

Summary

Introduction

Primary sarcopenia is a phenomenon of age-related loss of muscle mass and function affecting up to 30% of older adults[1]. Muscle loss in primary sarcopenia appears to be driven primarily by anabolic resistance. Secondary sarcopenia, such as the inflammatory muscle wasting of cancer, cardiac, and rheumatoid cachexia, appears to be driven by primarily catabolic processes. The UPS can be activated via Nuclear Factor-kappa B (NF-κB) and p38 Mitogen-Activated Protein Kinases (MAPK) - two major intracellular signaling pathways in skeletal muscle[15]. Instead, impaired anabolism appears to be the major source of muscle loss in primary sarcopenia. Unlike in RC, there is a large body of evidence demonstrating reduced testosterone, insulin-like growth factor 1, growth hormone and increased myostatin in age-related muscle loss[20]

Objectives

Methods

Results

Conclusion