Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction.

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague-Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ).

The IRE1/XBP1 signaling axis promotes skeletal muscle regeneration through a cell non-autonomous mechanism.

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in the endoplasmic reticulum. However, the role of individual arms of the UPR in skeletal muscle regeneration remain less understood.

MyD88-mediated signaling intercedes in neurogenic muscle atrophy through multiple mechanisms.

Skeletal muscle atrophy is a debilitating complication of many chronic disease states and disuse conditions including denervation. However, molecular and signaling mechanisms of muscle wasting remain less understood. Here, we demonstrate that the levels of several toll-like receptors (TLRs) and their downstream signaling adaptor, myeloid differentiation primary response 88 (MyD88), are induced in skeletal muscle of mice in response to sciatic nerve denervation.

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy.

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules.

The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia.

Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown.

PERK regulates skeletal muscle mass and contractile function in adult mice.

Skeletal muscle mass is regulated by the coordinated activation of several anabolic and catabolic pathways. The endoplasmic reticulum (ER) is a major site of protein folding and a reservoir for calcium ions. Accretion of misfolded proteins or depletion in calcium concentration causes stress in the ER, which leads to the activation of a signaling network known as the unfolded protein response (UPR).

MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, leads to severe muscle wasting and eventual death of the afflicted individuals, primarily due to respiratory failure. Deficit in myofiber regeneration, potentially due to an exhaustion of satellite cells, is one of the major pathological features of DMD. Myeloid differentiation primary response 88 (MyD88) is an adaptor protein that mediates activation of various inflammatory pathways in response to signaling from Toll-like receptors and interleukin-1 receptor.

TAK1 regulates skeletal muscle mass and mitochondrial function.

Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β-activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown.

Distinct roles of TRAF6 and TAK1 in the regulation of adipocyte survival, thermogenesis program, and high-fat diet-induced obesity.

Chronic low-grade inflammation, adipocyte hypertrophy, and glucose intolerance are common features of obesity and a risk factor for cancer. Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is an adaptor protein that also possesses a non-conventional E3 ubiquitin ligase activity. In response to receptor-mediated events, TRAF6 activates transforming growth factor-activated kinase 1 (TAK1), which leads to activation of the MAPK and nuclear factor-kappa B (NF-κB) signaling pathways.

The PERK arm of the unfolded protein response regulates satellite cell-mediated skeletal muscle regeneration.

Regeneration of skeletal muscle in adults is mediated by satellite stem cells. Accumulation of misfolded proteins triggers endoplasmic reticulum stress that leads to unfolded protein response (UPR). The UPR is relayed to the cell through the activation of PERK, IRE1/XBP1, and ATF6.

Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease.

Skeletal muscle is the most abundant tissue in the human body and can adapt its mass as a consequence of physical activity, metabolism, growth factors, and disease conditions. Skeletal muscle contains an extensive network of endoplasmic reticulum (ER), called sarcoplasmic reticulum, which plays an important role in the regulation of proteostasis and calcium homeostasis. In many cell types, environmental and genetic factors that disrupt ER function cause an accumulation of misfolded and unfolded proteins in the ER lumen that ultimately leads to ER stress.

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress.