Alterations in activin A–myostatin–follistatin system associate with disease activity in inflammatory myopathies

Abstract

Objectives The aim of this study was to investigate the systemic and skeletal muscle levels of atrophy-associated myokines in patients with idiopathic inflammatory myopathies (IIM) and their association with clinical characteristics of myositis. Methods A total of 94 IIM patients and 162 healthy controls were recruited. Of those, 20 IIM patients and 28 healthy controls underwent a muscle biopsy. Circulating concentrations of myostatin, follistatin, activin A and TGF-β1 were assessed by ELISA. The expression of myokines and associated genes involved in the myostatin signalling pathway in muscle tissue was determined by real-time PCR. Results We report decreased levels of circulating myostatin (median 1817 vs 2659 pg/ml; P = 0.003) and increased follistatin (1319 vs 1055 pg/ml; P = 0.028) in IIM compared with healthy controls. Activin A levels were also higher in IIM (414 vs 309 pg/ml; P = 0.0005) compared with controls. Myostatin was negatively correlated to muscle disease activity assessed by physician on visual analogue scale (MDA) (r = −0.289, P = 0.015) and positively to manual muscle testing of eight muscles (r = 0.366, P = 0.002). On the other hand, follistatin correlated positively with MDA (r = 0.235, P = 0.047). Gene expression analysis showed higher follistatin (P = 0.003) and myostatin inhibitor follistatin-like 3 protein (FSTL3) (P = 0.008) and lower expression of activin receptor type 1B (ALK4) (P = 0.034), signal transducer SMAD3 (P = 0.023) and atrophy marker atrogin-1 (P = 0.0009) in IIM muscle tissue compared with controls. Conclusion This study shows lower myostatin and higher follistatin levels in circulation and attenuated expression of myostatin pathway signalling components in skeletal muscle of patients with myositis, a newly emerging pattern of the activin A–myostatin–follistatin system in muscle wasting diseases.

Myostatin as a Biomarker of Muscle Wasting and other Pathologies-State of the Art and Knowledge Gaps

“…A similar mechanism emerges in idiopathic inflammatory myopathies. Vernerova et al, demonstrated that such disorders with decreased serum myostatin level associated with an increase of circulating follistatin concentration pose as a possible compensatory mechanism attempting to counteract muscle hypotrophy by inhibiting myostatin/ActRIIB signaling in such disorders [ 104 ]. All these novel findings greatly expand the understanding of myostatin in neuromuscular diseases and prove its viability as a biomarker in these conditions.…”

Myostatin and Markers of Bone Metabolism in Dermatomyositis

“…This investigation's nding of higher MSTN levels in DM patients compared to controls is in contrast to one study evaluating different myositis subtypes. Vernerova et al [9] could not reveal signi cant differences in serum levels of MSTN in their DM patients compared to healthy controls. However, comparison between these two studies is di cult because characteristics of patients are only given for the whole group of idiopathic in ammatory myopathy patients; no separate data of the included DM patients are shown.…”

“…Pathophysiological mechanisms of DM-associated muscle and bone strength loss are not well investigated in DM patients. Only one study [9] evaluated the above-mentioned regulators of muscle growth in DM patients so far. Thus, the aim of this study was to investigate the pathophysiological role of important factors regulating myogenesis and bone metabolism in patients with DM.…”

Role of Myokines in Myositis Pathogenesis and Their Potential to be New Therapeutic Targets in Idiopathic Inflammatory Myopathies

“…(ii) Follistatin gene transfer to sIBM patients-clinical trial, resulted in an improvement in muscle regeneration [117]. (iii) Follistatin high serum levels concomitant with decreased serum myostatin levels in IIM patients [118].…”

“…Vernerova et al reported higher follistatin and lower myostatin levels in circulation and attenuated expression of myostatin pathway signaling components in skeletal muscle in IIM patients compared with healthy controls [ 118 ].…”