The accumulation of muscle RING finger-1 in regenerating myofibers: Implications for muscle repair in immune-mediated necrotizing myopathy

Abstract

BackgroundMuscle RING finger-1 (MuRF-1) plays a key role in the degradation of skeletal muscle proteins. We hypothesize the involvement of MuRF-1 in immune-mediated necrotizing myopathy (IMNM).MethodsMuscle biopsies from patients with IMNM (n = 37) were analyzed and compared to biopsies from patients with dermatomyositis (DM, n = 13), dysferlinopathy (n = 9) and controls (n = 7) using immunostaining.ResultsMuRF-1 staining could be observed in IMNM, DM and dysferlinopathy biopsies, whereas the percentage of MuRF-1 positive myofibers was significantly higher in IMNM than in dysferlinopathy (p = 0.0448), and positively correlated with muscle weakness and disease activity in IMNM and DM. Surprisingly, MuRF-1 staining predominantly presented in regenerating fibers but not in atrophic fibers. Moreover, MuRF-1-positive fibers tended to be distributed around necrotic myofibers and myofibers with sarcolemma membrane attack complex deposition. Abundant MuRF-1 expression in IMNM and DM was associated with rapid activation of myogenesis after muscle injury, whereas relatively low expression of MuRF-1 in dysferlinopathy may be attributed to damaged muscle regeneration.ConclusionsMuRF-1 accumulated in regenerating myofibers, which may contribute to muscle injury repair in IMNM and DM. MuRF-1 staining may help clinicians differentiate IMNM and dysferlinopathy.

Association of the MuRF-1/TRIM63 polymorphism with muscle injuries in professional soccer players

“…Other studies have shown that increased expression of MuRF-1 after muscle damage can increase the ubiquitination process of damaged myofibrillar and sarcoplasmic proteins (Baehr et al, 2021;Yang et al, 2022), thus contributing to successful tissue repair and promoting faster recovery. However, it is hypothesized that the restricted affinity of proteins (MuRF-1 and titin) could affect the interactions between the contractile and structural properties of muscle fibers, the muscle regeneration process and contribute to a less resistant muscle.…”

“…MuRF-1, MuRF-2 and MuRF-3 proteins are a specific class of proteins expressed in striated and cardiac muscle tissues (Chen et al, 2012;Peris-Moreno et al, 2020). The MuRF-1 protein mediates a key role in the Ubiquitin Proteasome System (UPS), attaching ubiquitin polymers to deteriorated myofibrillar proteins after muscle damage (Centner et al, 2001;Yang et al, 2022). MuRF-1 is localized at the Z-and the M-line of the sarcomere, in which it has been found to interact and modulate the mechanical properties of titin (Baehr et al, 2021;Bodine et al, 2001).…”

“…This connection may provide stability and protection against muscle damage caused by eccentric damaging contractions from sports practice (Baumert et al, 2017). After this damaging process, coordinated actions are mediated by MuRF-1 and titin in the control of protein quality, protein degradation, and synthesis as well as in the process of structuring new myofibrils (Stefanetti et al, 2014;Yang et al, 2022).…”

Management of immune‐mediated necrotizing myopathy

“…We also consider checking the antibodies in patients who present with chronic progression since such cases have been rarely described, particularly in patients with younger onset. 6 These patients may have already had or may undergo simultaneous genetic testing for muscular dystrophy.…”

“…However, cases with slow progression over 6 months to years have also been described, particularly in pediatric patients, resembling muscular dystrophy. [3][4][5][6] Serum creatine kinase (CK) is elevated, oftentimes more than five times the upper limit of normal on presentation and typically higher than is seen with other IIMs. 7 Antibodies may be present against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or signal recognition peptide (SRP), or neither may be present (hereinafter referred to as seronegative).…”