scholarly journals Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia

2015 ◽  
Vol 290 (17) ◽  
pp. 11177-11187 ◽  
Author(s):  
Kleiton Augusto Santos Silva ◽  
Jiangling Dong ◽  
Yanjun Dong ◽  
Yanlan Dong ◽  
Nestor Schor ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Cancer Cachexia ◽  
Caspase 3 ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Supplementation of ketoacids contributes to the up-regulation of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin–proteasome systems in the muscle of 5/6 nephrectomised rats

2014 ◽  
Vol 111 (9) ◽  
pp. 1536-1548 ◽  
Author(s):  
Dong-Tao Wang ◽  
Lu Lu ◽  
Ying Shi ◽  
Zhen-Bo Geng ◽  
Yi Yin ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Atrophy ◽  
Caspase 3 ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Protein Diet ◽  
Down Regulation ◽  
Beneficial Effects ◽  
Phosphorylated Akt ◽  
Ubiquitin Proteasome

Ketoacids (KA) are known to improve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (CKD-LPD), but the mechanism of its preventive effects on muscle atrophy still remains unclear. Since muscle atrophy in CKD may be attributable to the down-regulation of the Wnt7a/Akt/p70S6K pathway and the activation of the ubiquitin–proteasome system (UPS) and the apoptotic signalling pathway, a hypothesis can readily be drawn that KA supplementation improves muscle mass by up-regulating the Wnt7a/Akt/p70S6K pathway and counteracting the activation of the UPS and caspase-3-dependent apoptosis in the muscle of CKD-LPD rats. Rats with 5/6 nephrectomy were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % KA for 24 weeks. Sham-operated rats with NPD intake were used as the control. The results demonstrated that KA supplementation improved protein synthesis and increased related mediators such as Wnt7a, phosphorylated Akt and p70S6K in the muscle of CKD-LPD rats. It also inhibited protein degradation, withheld the increase in ubiquitin and its ligases MAFbx (muscle atrophy F-box) and MuRF1 (muscle ring finger-1) as well as attenuated proteasome activity in the muscle of CKD-LPD rats. Moreover, KA supplementation gave rise to a reduction in DNA fragment, cleaved caspase-3 and 14 kDa actin fragment via the down-regulation of the Bax:Bcl-2 ratio in the muscle of CKD-LPD rats. The beneficial effects unveiled herein further consolidate that KA may be a better therapeutic strategy for muscle atrophy in CKD-LPD.

scholarly journals Increasing autophagy does not affect neurogenic muscle atrophy

2018 ◽  
Vol 28 (3) ◽  
Author(s):  
Eva Pigna ◽  
Krizia Sanna ◽  
Dario Coletti ◽  
Zhenlin Li ◽  
Ara Parlakian ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Autophagic Flux ◽  
Molecular Pathways ◽  
Muscle Loss ◽  
Relative Contribution ◽  
Ubiquitin Proteasome ◽  
Muscle Mass Loss ◽  
Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

Calpain and caspase-3 play required roles in immobilization-induced limb muscle atrophy

2013 ◽  
Vol 114 (10) ◽  
pp. 1482-1489 ◽  
Author(s):  
Erin E. Talbert ◽  
Ashley J. Smuder ◽  
Kisuk Min ◽  
Oh Sung Kwon ◽  
Scott K. Powers
Keyword(s):  
Muscle Atrophy ◽  
Caspase 3 ◽  
Respiratory Muscles ◽  
Ubiquitin Proteasome System ◽  
Type I ◽  
Disuse Atrophy ◽  
Limb Muscle ◽  
Disuse Muscle Atrophy ◽  
Ubiquitin Proteasome ◽  
Rat Soleus Muscle

Prolonged skeletal muscle inactivity results in a rapid decrease in fiber size, primarily due to accelerated proteolysis. Although several proteases are known to contribute to disuse muscle atrophy, the ubiquitin proteasome system is often considered the most important proteolytic system during many conditions that promote muscle wasting. Emerging evidence suggests that calpain and caspase-3 may also play key roles in inactivity-induced atrophy of respiratory muscles, but it remains unknown if these proteases are essential for disuse atrophy in limb skeletal muscles. Therefore, we tested the hypothesis that activation of both calpain and caspase-3 is required for locomotor muscle atrophy induced by hindlimb immobilization. Seven days of immobilization (i.e., limb casting) promoted significant atrophy in type I muscle fibers of the rat soleus muscle. Independent pharmacological inhibition of calpain or caspase-3 prevented this casting-induced atrophy. Interestingly, inhibition of calpain activity also prevented caspase-3 activation, and, conversely, inhibition of caspase-3 prevented calpain activation. These findings indicate that a regulatory cross talk exists between these proteases and provide the first evidence that the activation of calpain and caspase-3 is required for inactivity-induced limb muscle atrophy.

scholarly journals Pueraria lobata and Daidzein Reduce Cytotoxicity by Enhancing Ubiquitin-Proteasome System Function in SCA3-iPSC-Derived Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-18
Author(s):  
I-Cheng Chen ◽  
Kuo-Hsuan Chang ◽  
Yi-Jing Chen ◽  
Yi-Chun Chen ◽  
Guey-Jen Lee-Chen ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Caspase 3 ◽  
Neurodegenerative Disorder ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Pueraria Lobata ◽  
Protein Ubiquitination ◽  
Ubiquitin Proteasome

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ATXN3/MJD1 gene. The expanded CAG repeats encode a polyglutamine (polyQ) tract at the C-terminus of the ATXN3 protein. ATXN3 containing expanded polyQ forms aggregates, leading to subsequent cellular dysfunctions including an impaired ubiquitin-proteasome system (UPS). To investigate the pathogenesis of SCA3 and develop potential therapeutic strategies, we established induced pluripotent stem cell (iPSC) lines from SCA3 patients (SCA3-iPSC). Neurons derived from SCA3-iPSCs formed aggregates that are positive to the polyQ marker 1C2. Treatment with the proteasome inhibitor, MG132, on SCA3-iPSC-derived neurons downregulated proteasome activity, increased production of radical oxygen species (ROS), and upregulated the cleaved caspase 3 level and caspase 3 activity. This increased susceptibility to the proteasome inhibitor can be rescued by a Chinese herbal medicine (CHM) extract NH037 (from Pueraria lobata) and its constituent daidzein via upregulating proteasome activity and reducing protein ubiquitination, oxidative stress, cleaved caspase 3 level, and caspase 3 activity. Our results successfully recapitulate the key phenotypes of the neurons derived from SCA3 patients, as well as indicate the potential of NH037 and daidzein in the treatment for SCA3 patients.

scholarly journals The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia

2020 ◽  
Vol 111 (3) ◽  
pp. 570-579 ◽  
Author(s):  
Ying Zhang ◽  
Jiwei Wang ◽  
Xulin Wang ◽  
Tingting Gao ◽  
Hao Tian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Muscle Fiber ◽  
Cancer Cachexia ◽  
Ubiquitin Proteasome System ◽  
Muscle Loss ◽  
Fiber Morphology ◽  
Cross Sectional ◽  
Ubiquitin Proteasome

ABSTRACT Background Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. Objectives We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients’ clinical phenotypes. Methods We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. Results Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 μm2) and S groups (480 ± 135 μm2) compared with the N (1615 ± 388 μm2, both P < 0.05) and C groups (1219 ± 302 μm2, both P < 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. Conclusions The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.

The Ubiquitin/Proteasome System in Cancer Cachexia

2007 ◽  
pp. 503-508 ◽  
Author(s):  
Maurizio Muscaritoli ◽  
Maurizio Bossola ◽  
Giovanni Battista Doglietto ◽  
Filippo Rossi Fanelli
Keyword(s):  
Cancer Cachexia ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

scholarly journals Mutant Ubiquitin-Mediated β-Secretase Stability via Activation of Caspase-3 is Related to β-Amyloid Accumulation in Ischemic Striatum in Rats

2009 ◽  
Vol 30 (3) ◽  
pp. 566-575 ◽  
Author(s):  
Yong Zhang ◽  
Man Xiong ◽  
Ri-Qiang Yan ◽  
Feng-Yan Sun
Keyword(s):  
Caspase 3 ◽  
Ubiquitin Proteasome System ◽  
Artery Occlusion ◽  
Amyloid Accumulation ◽  
Ipsilateral Striatum ◽  
Ubiquitin Proteasome ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Stability ◽  
Cerebral Artery Occlusion

Previous studies have demonstrated that ischemic stroke increases β-amyloid (Aβ) production by increasing β-secretase (BACE1) through activation of caspase-3, and stimulates generation of mutant ubiquitin (UBB+1) in rat brains. In this study, we examined whether caspase-3 activation participates in the regulation of UBB+1 generation and UBB+1-mediated BACE1 stability in ischemic injured brains. The results showed that UBB+1 and activated caspase-3-immunopositive-stained cells were time dependently increased in the ipsilateral striatum of rat brains after middle cerebral artery occlusion. UBB+1-immunopositive cells could be co-stained with caspase-3, Aβ (UBB+1–Aβ), and BACE1 (UBB+1–BACE1). BACE1 protein could also be pulled down by immunoprecipitation with UBB+1 antibody. Z-DEVD-FMK (DEVD), a caspase-3 inhibitor, significantly decreased the level of UBB+1 protein and the number of UBB+1–Aβ and UBB+1–BACE1 double-stained cells in the ischemic striatum, as well as the level of UBB+1/BACE1 protein complex. We conclude that activation of caspase-3 might be upstream of UBB+1 formation and that excessive UBB+1 could bind to BACE1 and increase the stability of BACE1, thereby increasing Aβ in ischemic injured brains. These results suggest new biological and pathological effects of caspases and regulation of the ubiquitin–proteasome system in the brain. Our results provide new therapeutic targets to prevent further neurodegeneration in patients after stroke.

scholarly journals Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

2015 ◽  
Vol 309 (7) ◽  
pp. E651-E662 ◽  
Author(s):  
Tatsuro Egawa ◽  
Ayumi Goto ◽  
Yoshitaka Ohno ◽  
Shingo Yokoyama ◽  
Akihiro Ikuta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Degradation ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Mass ◽  
Ubiquitin Proteasome System ◽  
Hindlimb Unloading ◽  
Slow Twitch Muscle ◽  
Ubiquitin Proteasome ◽  
Slow Twitch

AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT ( n = 24) and AMPK-DN ( n = 24) mice were randomly divided into two groups: an untreated preexperimental control group ( n = 12 in each group) and an unloading ( n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ∼30% in WT mice by hindlimb unloading and by ∼20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of κBα, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system.

scholarly journals Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia

2018 ◽  
Vol 28 (2) ◽  
Author(s):  
Jeffrey S. Damrauer ◽  
Michael E. Stadler ◽  
Swarnali Acharyya ◽  
Albert S. Baldwin ◽  
Marion E. Couch ◽  
...  
Keyword(s):  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Tumor Burden ◽  
Cancer Treatments ◽  
Colon 26 ◽  
Reduce Tumor Burden ◽  
High Incidence ◽  
Ubiquitin Proteasome ◽  
Chemotherapy Agents

A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-κB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-κB signaling pathway.

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