Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications

Agrawal, Akanksha; Suryakumar, Geetha; Rathor, Richa

doi:10.1007/s12079-018-0477-z

Cited by 47 publications

(46 citation statements)

References 157 publications

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“…Indeed, increased intracellular Ca 2+ activates calpains, calcium-activated proteases, that play a pivotal role in the initiation of most proteolytic pathways such as the ubiquitin-proteasome pathway [43]. Furthermore, several studies show that intracellular calcium increase stimulates the mitochondrial apoptotic process through the activation of proapoptotic protein Bax which favors the formation of the mitochondrial permeability transition pore (mPTP) allowing the release of cytochrome C from mitochondria and promoting cell apoptosis [44].…”

Section: Calcium Homeostasismentioning

confidence: 99%

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Conte

Bresciani

Rizzi

et al. 2020

IJMS

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Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.

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Section: Calcium Homeostasismentioning

confidence: 99%

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Conte

Bresciani

Rizzi

et al. 2020

IJMS

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“…The ER is an important organelle for the regulation of intracellular Ca 2+ stability, and excessive imbalance in Ca 2+ homeostasis can eventually lead to ERS 16 . In fact, sustained ERS has been reported to drive muscle atrophy 39 .…”

Section: Nnc-55 Induces Ers and Intracellular Ca 2+ Disordermentioning

confidence: 99%

“…Skeletal muscle contains a large amount of endoplasmic reticulum (ER), called the sarcoplasmic reticulum (SR), which plays an important role in regulating the internal stability of skeletal muscle. Endoplasmic reticulum stress (ERS) can be caused by an imbalance of Ca 2+ , excess reactive oxygen species, the accumulation of misfolded proteins, and many other perturbations that disrupt cell homeostasis [16][17][18] . There are three ERresident proximal sensors of unfolded proteins and ERS: ATF6, IRE1, and PERK 19,20 .…”

Section: Introductionmentioning

confidence: 99%

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Hao

et al. 2020

Cell Death Dis

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Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca 2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h −/− (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

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“…Other mechanisms have recently been shown to be involved in cancer-related sarcopenia, such as epigenetic alterations involving bromodomain protein BRD4 (Segatto et al, 2017) and calcium homeostasis involving ryanodine receptors (A. Agrawal, Suryakumar, & Rathor, 2018;Waning et al, 2015). Endocrine and metabolic factors also play a pivotal role in the pathogenesis of sarcopenia.…”

Section: Sarcopenia Definition and Modalities Of Body Composition Anamentioning

confidence: 99%

Body composition and sarcopenia: The next-generation of personalized oncology and pharmacology?

Hilmi

Jouinot

Burns

et al. 2019

Pharmacology & Therapeutics

111

112

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Body composition has gained increasing attention in oncology in recent years due to fact that sarcopenia has been revealed to be a strong prognostic indicator for survival across multiple stages and cancer types and a predictive factor for toxicity and surgery complications. Accumulating evidence over the last decade has unraveled the "pharmacology" of sarcopenia. Lean body mass may be more relevant to define drug dosing than the "classical" body surface area or flat-fixed dosing in patients with cancer. Since sarcopenia has a major impact on patient survival and quality of life, therapeutic interventions aiming at reducing muscle loss have been developed and are being prospectively evaluated in randomized controlled trials. It is now acknowledged that this supportive care dimension of oncological management is essential to ensure the success of any anticancer treatment. The field of sarcopenia and body composition in cancer is developing quickly, with (i) the newly identified concept of sarcopenic obesity defined as a specific pathophysiological entity, (ii) unsolved issues regarding the best evaluation modalities and cutoff for definition of sarcopenia on imaging, (iii) first results from clinical trials evaluating physical activity, and (iv) emerging body-compositiontailored drug administration schemes. In this context, we propose a comprehensive review providing a panoramic approach of the clinical, pharmacological and therapeutic implications of sarcopenia and body composition in oncology.

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Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications

Cited by 47 publications

References 157 publications

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Body composition and sarcopenia: The next-generation of personalized oncology and pharmacology?

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