Compensatory anabolic signaling in the sarcopenia of experimental chronic arthritis

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.

Collagen‐induced arthritis as an animal model of rheumatoid cachexia

“…Our previous research demonstrated that these animals present up to a 30% decrease in myofiber diameter after 45 days of disease induction . In addition, a recently published study with autoimmune monoarthritis by AIA has shown several molecular analyses for muscle wasting observed in rabbits, including increased GA atrogin‐1 and MURF‐1 expression . The present study confirms that animals had muscle loss even if they did not lose weight.…”

“…22 In addition, a recently published study with autoimmune monoarthritis by AIA has shown several molecular analyses for muscle wasting observed in rabbits, including increased GA atrogin-1 and MURF-1 expression. 40 The present study confirms that animals had muscle loss even if they did not lose weight. It was observed by the less weigh in tibialis anterior and gastrocnemius muscles in the CIA group (decrease of 25 and 24%, respectively).…”

“…Despite that lipid metabolism is relevant in RA, the response to treatment is also due to adipose tissue role as a potent source of cytokines and adipokines including TNF . Furthermore, a recently published study with Antigen‐Induced Arthritis (AIA) in rabbits has shown increased in C‐reactive protein and GA IL‐1beta also corroborates to the inhibitory effect of inflammation on animal fat lipogenesis as well as muscle loss. Furthermore, there are few RA patients that develop severe arthritis that are the most similar to our animal model arthritis development.…”

Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia

“…Aging is associated with a chronic state of systemic low‐grade inflammation, characterized by increased plasma levels of pro‐inflammatory mediators like TNF‐α and IL‐6, which are able to stimulate proteolysis mainly via UPR, as previously described for cancer cachexia . However, the role of UPR in sarcopenia is still contentious . Some studies have described an up‐regulation of components of the UPR in sarcopenia while other have shown a down‐regulation or no differences …”

Profiles Associated with Sarcopenia in Hepatoma Patients Underwent Transcatheter Arterial Chemoembolization: A Data‐Mining Analysis

“…Sarcopenia is classified by its etiology into primary or secondary sarcopenia. Primary sarcopenia is a phenomenon of age‐related loss of muscle mass and function, affecting up to 30% of older adults [4]. Secondary sarcopenia is the reduced muscle mass and strength that accompanies an underlying disease.…”