scholarly journals AMPK mediates early activation of the unfolded protein response through a positive feedback loop in palmitate-treated muscle cells

2021 ◽  
Author(s):  
Jing Gong ◽  
Lu Wang ◽  
Wuchen Tao ◽  
Zonghan Liu ◽  
Wenjiong Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Positive Feedback Loop ◽  
Ampk Signaling ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Activation of the unfolded protein response (UPR) is closely associated with the pathogenesis of many metabolic diseases including obesity and type 2 diabetes. There is increasing evidence for the interdependence of the UPR and metabolic signaling pathways. The AMP-activated protein kinase (AMPK) signaling pathway controls energy balance in eukaryotes. The aim of this study was to investigate the possible interaction between AMPK signaling and the UPR in muscle cells exposed to a saturated fatty acid, as well as the underlying mechanism. The UPR was induced in C2C12 myotubes by treatment with palmitate along with activation of AMPK signaling. Inhibiting the AMPK pathway with compound C attenuated palmitate-induced UPR activation, while inhibiting the UPR with taurourdodeoxycholic acid alleviated palmitate-induced AMPK activation, suggesting a positive feedback loop between the UPR and AMPK. Additionally, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide, an AMPK agonist, caused a dose- and time-dependent upregulation of genes related to the UPR, including activating transcription factor (ATF)4, binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible protein (GADD)34. These results provide the first evidence for the involvement of AMPK signaling in the early activation of the UPR induced by saturated fatty acid in skeletal muscle, and suggest that physiologic or pharmacologic activation of the AMPK pathway (ie, by exercise or metformin, respectively) can promote skeletal muscle health and function and thus improve quality of life for individuals with metabolic disorder due to a high-fat diet or obesity.

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

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

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. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

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

2021 ◽  
Vol 23 (1) ◽  
pp. 169
Author(s):  
Lisa A. Walter ◽  
Lauren P. Blake ◽  
Yann S. Gallot ◽  
Charles J. Arends ◽  
Randall S. Sozio ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sciatic Nerve ◽  
Neuromuscular Junction ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Sprague Dawley ◽  
Unfolded Protein ◽  
Potential Therapeutic Role ◽  
The Unfolded Protein Response ◽  
Protein Response

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). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

scholarly journals Grandpaternal-induced transgenerational dietary reprogramming of the unfolded protein response in skeletal muscle

2017 ◽  
Vol 6 (7) ◽  
pp. 621-630 ◽  
Author(s):  
Petter S. Alm ◽  
Thais de Castro Barbosa ◽  
Romain Barrès ◽  
Anna Krook ◽  
Juleen R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

2019 ◽  
Vol 21 (1) ◽  
pp. 182 ◽  
Author(s):  
Yukako Tokutake ◽  
Keita Yamada ◽  
Satoko Hayashi ◽  
Wataru Arai ◽  
Takafumi Watanabe ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Cyclin Dependent Kinase ◽  
Early Differentiation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

scholarly journals Attenuated activation of the unfolded protein response following exercise in skeletal muscle of older adults

Aging ◽  
2019 ◽  
Vol 11 (18) ◽  
pp. 7587-7604 ◽  
Author(s):  
Corey R. Hart ◽  
Zachary C. Ryan ◽  
Kyle T. Pfaffenbach ◽  
Surendra Dasari ◽  
Mojtaba Parvizi ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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