Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner

Ogilvie, Hannah; Cacciani, Nicola; Akkad, Hazem; Larsson, Lars

doi:10.3389/fphys.2016.00417

Cited by 9 publications

(10 citation statements)

References 54 publications

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“…They display mild hyperglycemia and damaged glucose tolerance, while being normotensive and non-obese [17]. Besides the insulin-sensitizing effect, the role of BGP-15 in alleviating ventilation-induced diaphragm dysfunction has been examined on Sprague-Dawley rats [40]. The advantage of these rats is their calmness and easy handling [41].…”

Section: Animal Modelsmentioning

confidence: 99%

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

et al. 2020

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BGP-15 is a new insulin sensitizer drug candidate, which was developed by Hungarian researchers. In recent years, numerous research groups have studied its beneficial effects. It is effective in the treatment of insulin resistance and it has protective effects in Duchenne muscular dystrophy, diastolic dysfunction, tachycardia, heart failure, and atrial fibrillation, and it can alleviate cardiotoxicity. BGP-15 exhibits chemoprotective properties in different cytostatic therapies, and has also proven to be photoprotective. It can additionally have advantageous effects in mitochondrial-stress-related diseases. Although the precise mechanism of the effect is still unknown to us, we know that the molecule is a PARP inhibitor, chaperone co-inducer, reduces ROS production, and is able to remodel the organization of cholesterol-rich membrane domains. In the following review, our aim was to summarize the investigated molecular mechanisms and pharmacological effects of this potential API. The main objective was to present the wide pharmacological potentials of this chemical agent.

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Section: Animal Modelsmentioning

confidence: 99%

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

et al. 2020

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“…Currently, there is no approved treatment against cachexia, despite many adjuvant therapeutics having been clinically evaluated (reviewed recently in [ 24 ]) Targeting the mitochondria could be therapeutically advantageous in this regard since they appear implicit in IRI-induced skeletal myopathy. One potential therapeutic candidate is the small molecule BGP-15, a hydroximic acid derivative nicotinic acid-amidoxime [ 25 ], which has demonstrated therapeutic potential in treating skeletal myopathy associated with Duchenne Muscular Dystrophy [ 26 , 27 ], ventilation-induced diaphragm dysfunction [ 28 , 29 , 30 , 31 ], sarcopenia [ 32 ], diabetes [ 33 , 34 , 35 ] and oxaliplatin treatment [ 36 ]. BGP-15 inhibits poly-(ADP-ribose) polymerase-1 (PARP-1) [ 37 ], a repressor of mitochondrial function [ 38 , 39 ], and co-induces heat shock protein-70 (HSP-70) [ 40 , 41 ], which increases mitochondrial content, function and oxidative capacity [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction

Campelj

Timpani

Petersen

et al. 2020

Cancers

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Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.

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“…In animals treated with BGP‐15 (n = 13), 100% survival was observed after 5, 8, and 10 days exposure to the ICU condition. In controls, we have also included rats exposed to the ICU condition at other durations than 5, 8 and 10 days, that is, results included from previous studies . The logrank statistic showed a significant ( P < .01) survival benefit with BGP‐15 (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Thirty‐six adult female Sprague‐Dawley rats were divided into one sham‐operated control group (n = 10) and the six experimental groups exposed to deep sedation, CMV, neuromuscular blockade (NMB) for 5 days with BGP‐15 treatment (5d + BGP‐15, n = 4) and without BGP‐15 (5d, n = 6), 8 days with BGP‐15 treatment (8d + BGP‐15, n = 3) and without BGP‐15 treatment (8d, n = 3), and 10 days with BGP‐15 (10d + BGP‐15, n = 4) and without BGP‐15 (10d, n = 6). For survival data in control rats, we also included results from other rats exposed to the ICU condition at other durations than 5, 8 and 10 days longer than 2 days (total number of controls, 30) included in previous studies …”

Section: Methodsmentioning

confidence: 99%

Chaperone co‐inducer BGP‐15 mitigates early contractile dysfunction of the soleus muscle in a rat ICU model

Cacciani

Salah

et al. 2019

Acta Physiologica

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Aim Critical illness myopathy (CIM) represents a common consequence of modern intensive care, negatively impacting patient health and significantly increasing health care costs; however, there is no treatment available apart from symptomatic and supportive interventions. The chaperone co‐inducer BGP‐15 has previously been shown to have a positive effect on the diaphragm in rats exposed to the intensive care unit (ICU) condition. In this study, we aim to explore the effects of BGP‐15 on a limb muscle (soleus muscle) in response to the ICU condition. Methods Sprague‐Dawley rats were subjected to the ICU condition for 5, 8 and 10 days and compared with untreated sham‐operated controls. Results BGP‐15 significantly improved soleus muscle fibre force after 5 days exposure to the ICU condition. This improvement was associated with the protection of myosin from post‐translational myosin modifications, improved mitochondrial structure/biogenesis and reduced the expression of MuRF1 and Fbxo31 E3 ligases. At longer durations (8 and 10 days), BGP‐15 had no protective effect when the hallmark of CIM had become manifest, that is, preferential loss of myosin. Unrelated to the effects on skeletal muscle, BGP‐15 had a strong positive effect on survival compared with untreated animals. Conclusions BGP‐15 treatment improved soleus muscle fibre and motor protein function after 5 days exposure to the ICU condition, but not at longer durations (8 and 10 days) when the preferential loss of myosin was manifest. Thus, long‐term CIM interventions targeting limb muscle fibre/myosin force generation capacity need to consider both the post‐translational modifications and the loss of myosin.

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Targeting Heat Shock Proteins Mitigates Ventilator Induced Diaphragm Muscle Dysfunction in an Age-Dependent Manner

Cited by 9 publications

References 54 publications

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

Pharmacological Overview of the BGP-15 Chemical Agent as a New Drug Candidate for the Treatment of Symptoms of Metabolic Syndrome

The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction

Chaperone co‐inducer BGP‐15 mitigates early contractile dysfunction of the soleus muscle in a rat ICU model

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