Electrical Stimulation Prevents Preferential Skeletal Muscle Myosin Loss in Steroid-Denervation Rats

Yamada, Takashi; Himori, Koichi; Tatebayashi, Daisuke; Yamada, Ryotaro; Ashida, Yuki; Imai, Tomihiro; Akatsuka, Masayuki; Masuda, Yoshiki; Kanzaki, Koji; Watanabe, Daiki; Wada, Masanobu; Westerblad, Håkan; Lanner, Johanna T.

doi:10.3389/fphys.2018.01111

Cited by 10 publications

(12 citation statements)

References 49 publications

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“…Altered mechano‐signalling seems involved in triggering a major part of selective myosin loss in experimental CIM models, and passive mechanical loading of the muscle partially ameliorates the CIM phenotype. Similar results were obtained using S‐D rat model; mechanical load induced by neuromuscular electrical stimulation (NMES) prevents myofibrillar dysfunction and preferential skeletal muscle myosin loss . ICU‐based NMES has recently been introduced for the treatment of CIM.…”

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confidence: 60%

BGP‐15: A potential therapeutic agent for critical illness myopathy

Yamada

2020

Acta Physiologica

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In the current issue of Acta Physiologica, Larsson and colleagues examined the effect of chaperone co-inducer BGP-15 on impaired contractile function of the slow-twitch soleus muscles in a rat intensive care unit (ICU) model. 1 They found that BGP-15 improves myofibrillar function in the soleus muscle after 5 days exposure to the ICU condition, which is accompanied by improved mitochondrial morphology/biogenesis and reduced oxidative post-translational modifications (PTMs) of myosin molecules. These findings highlight the critical role of mitochondrial oxidative stress-induced myosin PTMs in myofibrillar dysfunction at the early stage of ICU admission and indicate BGP-15 as a potent candidate for therapeutic application in ICU-acquired weakness.With the significant improvements in modern intensive care medicine, mortality of ICU patients has dropped; on the other hand, it increases incidence of muscle weakness and paralysis, typically referred to as critical illness myopathy (CIM). Triggering factors for CIM include sepsis, mechanical ventilation, muscle unloading, steroid treatment or denervation. 2 CIM is marked by muscle atrophy, a preferential myosin loss, and reduction of electrical excitability. CIM is not reproduced only by disuse, denervation, steroid treatment or sepsis, however the combination of denervation and a highdose steroid induces a selective loss of myosin and membrane hypoexcitability. This steroid-denervation (S-D) model was first developed over 30 years ago and has long been used to mimic the muscle pathology found in CIM patients.During the past decade, Larsson and colleagues have significantly contributed to improve our understanding of the mechanism underlying CIM using unique experimental porcine and rodent ICU models that allow mechanical ventilation with pharmacological post-synaptic neuromuscular blockade for several weeks. 2 Altered mechano-signalling seems involved in triggering a major part of selective myosin loss in experimental CIM models, and passive mechanical loading of the muscle partially ameliorates the CIM phenotype. Similar results were obtained using S-D rat model; mechanical load induced by neuromuscular electrical stimulation (NMES) prevents myofibrillar dysfunction and preferential skeletal muscle myosin loss. 3 ICU-based NMES has recently been introduced for the treatment of CIM. However, owing to the heterogeneity of critically ill patients and also reduced electrical excitability of target skeletal muscles, the effectiveness of NMES for CIM prevention remains to be determined. Accordingly, the development of an effective pharmacological intervention is required for treating patients with CIM.An ICU model established by Larsson and colleagues also provides novel insights regarding the time course changes in contractile function as well as the molecular alterations in skeletal muscles, and highlights the PTMs of myosin as a causative factor in the myofibrillar dysfunction observed at the early stage of CIM. Heat shock protein (HSP) 72 is one of the most abundant HSP...

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confidence: 60%

BGP‐15: A potential therapeutic agent for critical illness myopathy

Yamada

2020

Acta Physiologica

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“…DEX was dissolved in saline at 2 mg/ml and injected intraperitoneally (5 mg/kg) everyday for 7 days. ES training was initiated immediately after DEN or the first DEX injection and was carried out for 7 consecutive days as described previously [28]. Rats were anesthetized by isoflurane inhalation and were placed supine on a platform and their left foot was secured in a foot plate connected to a torque sensor (S-14154, Takei Scientific Instruments) at an angle of 0 degree plantarflexion, with the right legs serving as control.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have shown reduced in situ force production accompanied by decreases in P max and MyHC content, and upregulation of ROS/RNS producing enzymes in steroid-denervation (S-D) rats, where animals were exposed to a combination of DEN and DEX treatment [28]. Furthermore, mechanical loading evoked by neuromuscular electrical stimulation (ES) prevented myofibrillar dysfunction and these molecular alterations in S-D rats.…”

Section: Introductionmentioning

confidence: 99%

Myofibrillar function differs markedly between denervated and dexamethasone-treated rat skeletal muscles: Role of mechanical load

et al. 2019

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Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.

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“…Intriguingly, denervation (DEN), and concomintant treatment of dexamethason (DEX), a synthetic glucocorticoid, produces characteristic pathologic feature of severe muscle atrophy, and preferential myosin depletion, although DEX treatment alone elicites muscle atrophy without loss of myosin (Rouleau et al, 1987;Mozaffar et al, 2007;Yamada et al, 2018Yamada et al, , 2019. Given that CCX results in increased levels of glucocorticoid (Tanaka et al, 1990), these data imply that not only CCX but also inactivity would be necessary to induce selective loss of myosin, which may explain the conflicting findings regarding the levels of MyHC expression in CCX muscles.…”

Section: Introductionmentioning

confidence: 99%

Cancer Cachexia Induces Preferential Skeletal Muscle Myosin Loss When Combined With Denervation

et al. 2020

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Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (−69%) that was significantly lower than DEN (−53%) or CCX (−36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.

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Electrical Stimulation Prevents Preferential Skeletal Muscle Myosin Loss in Steroid-Denervation Rats

Cited by 10 publications

References 49 publications

BGP‐15: A potential therapeutic agent for critical illness myopathy

BGP‐15: A potential therapeutic agent for critical illness myopathy

Myofibrillar function differs markedly between denervated and dexamethasone-treated rat skeletal muscles: Role of mechanical load

Cancer Cachexia Induces Preferential Skeletal Muscle Myosin Loss When Combined With Denervation

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