Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy

Abstract

Background Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteolytic activities of two muscle-specific E3 ubiquitin ligases: muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx or Atrogin-1). The nuclear factor-kappa B (NF-κB) pathway has emerged as a critical signaling network in skeletal muscle atrophy and has become a prime therapeutic target for the treatment of muscle diseases. Unfortunately, none of the NF-κB targeting drugs are currently being used to treat these diseases, likely because of our limited knowledge and specificity, for muscle biology and disease. The cellular inhibitor of apoptosis 1 (cIAP1) protein is a positive regulator of tumor necrosis factor alpha (TNFα)-mediated classical NF-κB signaling, and cIAP1 loss has been shown to enhance muscle regeneration during acute and chronic injury. Methods Sciatic nerve transection in wild-type, cIAP1-null and Smac mimetic compound (SMC)-treated mice was performed to investigate the role of cIAP1 in denervation-induced atrophy. Genetic in vitro models of C2C12 myoblasts and primary myoblasts were also used to examine the role of classical NF-κB activity in cIAP1-induced myotube atrophy. Results We found that cIAP1 expression was upregulated in denervated muscles compared to non-denervated controls 14 days after denervation. Genetic and pharmacological loss of cIAP1 attenuated denervation-induced muscle atrophy and overexpression of cIAP1 in myotubes was sufficient to induce atrophy. The induction of myotube atrophy by cIAP1 was attenuated when the classical NF-κB signaling pathway was inhibited. Conclusions These results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases. Electronic supplementary material The online version of this article (10.1186/s13395-019-0201-6) contains supplementary material, which is available to authorized users.

Isoquercitrin Delays Denervated Soleus Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation

“…Furthermore, our study revealed that isoquercitrin inhibits target muscle atrophy following denervation, which is mainly characterized as inhibiting the reduction of the wet weight ratio and muscle fiber cross-sectional area of the denervated target muscle. The ubiquitin-proteasome system plays an important role in various muscle atrophies, including those associated with denervation, disuse, tumor cachexia, diabetes, and various chronic inflammatory conditions (Gao et al, 2018;Lala-Tabbert et al, 2019;Han et al, 2020;Nguyen et al, 2020). MAFbx and MuRF1 are two muscle-specific E3 ubiquitin ligases that are increased in various muscle atrophies and are confirmed as suitable markers of muscle atrophy (Bodine and Baehr, 2014).…”

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease

“…Fbxo32 levels were also regulated by a cellular inhibitor of apoptosis 1 (cIAP1) through an Ikkβ-dependent mechanism. Suppression of NFkB signaling or cIAP inhibition through smac mimetic compounds (SMCs), such as LCL161 (which is a cIAP antagonists that promotes the premature degradation of the proteins), could serve as a potential therapy for skeletal muscle atrophy [ 67 ].…”

Microarray Analysis of Gene Expression Provides New Insights Into Denervation-Induced Skeletal Muscle Atrophy

“…Animals with sciatic nerve transection have been commonly chosen as a study model for denervation-induced skeletal muscle atrophy (Madaro et al, 2018; Lala-Tabbert et al, 2019). Once sciatic nerve is transected, target muscles will lose their function of “muscle pump” due to the loss of nerve innervation, which leads to relatively reduced perfusion of target muscles, facilitating skeletal muscle atrophy (Laughlin, 1987; Marra et al, 2015).…”

“…Once sciatic nerve is transected, target muscles will lose their function of “muscle pump” due to the loss of nerve innervation, which leads to relatively reduced perfusion of target muscles, facilitating skeletal muscle atrophy (Laughlin, 1987; Marra et al, 2015). This type of skeletal muscle atrophy is regulated by different molecular mediators (Tang et al, 2014; Li et al, 2017; Choi et al, 2018; Pigna et al, 2018; Lala-Tabbert et al, 2019), but the issue of how molecular mediators are deliberately orchestrated to activate atrophic programs is to be systematically addressed. The purpose of this study was to furnish a global perspective of transcriptional regulation for denervation-induced skeletal muscle atrophy.…”