Activation of the Wnt/β-catenin signaling cascade after traumatic nerve injury

Abstract

Recent data have shown that preservation of the neuromuscular junction (NMJ) after traumatic nerve injury helps to improve functional recovery with surgical repair via matrix metalloproteinase-3 (MMP3) blockade. As such, we sought to explore additional pathways that may augment this response. Wnt3a has been shown to inhibit acetylcholine receptor (AChR) clustering via β-catenin-dependent signaling in the development of the NMJ. Therefore, we hypothesized that Wnt3a and β-catenin are associated with NMJ destabilization following traumatic denervation. A critical size nerve defect was created by excising a 10-mm segment of the sciatic nerve in mice. Denervated muscles were then harvested at multiple time points for immunofluorescence staining, quantitative real-time PCR, and western blot analysis for Wnt3a and β-catenin levels. Moreover, a novel Wnt/β-catenin transgenic reporter mouse line was utilized to support our hypothesis of Wnt activation after traumatic nerve injury. The expression of Wnt3a mRNA was significantly increased by 2 weeks post-injury and remained upregulated for 2 months. Additionally, β-catenin was activated at 2 months post-injury relative to controls. Correspondingly, immunohistochemical analysis of denervated transgenic mouse line TCF/Lef:H2B-GFP muscles demonstrated that the number of GFP-positive cells was increased at the motor endplate band. These collective data support that post-synaptic AChRs destabilize after denervation by a process that involves the Wnt/β-catenin pathway. As such, this pathway serves as a potential therapeutic target to prevent the motor endplate degeneration that occurs following traumatic nerve injury.

Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle

“…Impaired neuromuscular function, due to NMJ injury, is central to a number of diseases and traumas that affect muscle mass and force production, causing impairments in voluntary movement [1–4] While the mechanism(s) underlying deterioration in neuromuscular function and NMJ are still being uncovered, excessive generation of mtROS and consequential oxidative stress predominate [1,7,8,56] However, until now, there has been no therapeutics that directly target mitochondria to preserve neuromuscular integrity. In this study, we sought to elucidate the consequence(s) of IR injury on mitochondrial oxidative status and its impact on skeletal muscle and motor nerve function by employing a model directly relevant to usage of a tourniquet to control blood flow in certain clinical procedures in humans.…”

“…Conditions in which neuromuscular function is compromised, such as amyotrophic lateral sclerosis [1], aging [2], muscular dystrophies [3] and traumatic injuries [4], are often characterized by deterioration of NMJ. In particular, following certain types of surgeries or as a first response to traumatic injury, in which a tourniquet is used to control blood flow, skeletal muscle and motor nerves are often damaged by ischemia reperfusion (IR), caused by interruption in tissue perfusion and subsequent restoration of blood flow.…”

Secreted Frizzled-Related Protein 5 (SFRP5) protects ATDC5 cells against LPS-induced inflammation and apoptosis via inhibiting Wnt5a/JNK pathway

“…Wnt family proteins are a class of morphogens involved in embryonic skeletal formation, tissue repair, brosis and joint homeostasis (17). Wnt regulates multiple signaling cascades, including the canonical Wnt-β catenin pathway, which is usually quiescent in many adult organs but can be activated in response to injury (18,19). In the pathogenesis of OA, activation of canonical Wnt signaling is observed in both articular cartilage and synovium following injury, with up-regulated expression of both Wnt ligands and target genes (20,21).…”

Neuromuscular junction degeneration in muscle wasting

“…A recent bioinformatics screen of aging-related alterations of gene expression in humans identified Slit2 to be significantly associated with physical capacity across 116 samples [34]. Furthermore, these data highlight a well established [2] but complex role [35,36] of wnt signaling in neuromuscular junction formation and maintenance as well as after traumatic injury [37]. The earlier mentioned screen of aging related alterations of gene expression in humans [34] also identified Amotl2.…”