The Stress Protein/Chaperone Grp94 Counteracts Muscle Disuse Atrophy by Stabilizing Subsarcolemmal Neuronal Nitric Oxide Synthase

Vitadello, Maurizio; Gherardini, Jennifer; Gorza, Luisa

doi:10.1089/ars.2012.4794

Cited by 25 publications

(140 citation statements)

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“…The few studies conducted in human observed that carbonylated protein levels did not change in the vastus lateralis after 8 and 14 days of bed rest [66,67], but became higher after 35 days [66]. In rodents, some studies reported an increase of carbonylated proteins in the soleus during the first week of hindlimb unloading [57,[68][69][70], whereas other reports did not observed such effect after 3, 7 and 14 days of hindlimb unloading [53,60,62]. A more restricted number of studies focused on the effects of immobilization on α,β-unsaturated aldehydes (e.g., 4-HNE, MDA), markers of lipid peroxidation.…”

Section: Skeletal Muscle Oxidative Stress In Immobilization and Physimentioning

confidence: 99%

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

Pierre

Appriou

Gratas-Delamarche

et al. 2016

Free Radical Biology and Medicine

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In the literature, the terms physical inactivity and immobilization are largely used as synonyms. The present review emphasizes the need to establish a clear distinction between these two situations. Physical inactivity is a behavior characterized by a lack of physical activity, whereas immobilization is a deprivation of movement for medical purpose. In agreement with these definitions, appropriate models exist to study either physical inactivity or immobilization, leading thereby to distinct conclusions. In this review, we examine the involvement of oxidative stress in skeletal muscle insulin resistance and atrophy induced by, respectively, physical inactivity and immobilization. A large body of evidence demonstrates that immobilization-induced atrophy depends on the chronic overproduction of reactive oxygen and nitrogen species (RONS). On the other hand, the involvement of RONS in physical inactivity-induced insulin resistance has not been investigated. This observation outlines the need to elucidate the mechanism by which physical inactivity promotes insulin resistance.

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Section: Skeletal Muscle Oxidative Stress In Immobilization and Physimentioning

confidence: 99%

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

Pierre

Appriou

Gratas-Delamarche

et al. 2016

Free Radical Biology and Medicine

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“…Decreased nNOS protein localization at the sarcolemma characterizes several human neuromuscular disorders, among which are muscle dystrophies and non‐inherited diseases . Investigations on experimental animal models that aimed to reproduce muscle atrophy induced by unloading, or denervation, demonstrated that the selective loss of nNOS from sarcolemma occurred concomitantly with increased accumulation of the active enzyme in the sarcoplasm , where it fostered myofiber atrophy by increasing activity of the FoxO3 transcription factor . Muscle atrophy secondary to unloading or denervation is very slight or absent in nNOS‐KO mice or after in vivo inhibition of the enzyme .…”

Section: Introductionmentioning

confidence: 99%

“…Investigations on experimental animal models that aimed to reproduce muscle atrophy induced by unloading, or denervation, demonstrated that the selective loss of nNOS from sarcolemma occurred concomitantly with increased accumulation of the active enzyme in the sarcoplasm , where it fostered myofiber atrophy by increasing activity of the FoxO3 transcription factor . Muscle atrophy secondary to unloading or denervation is very slight or absent in nNOS‐KO mice or after in vivo inhibition of the enzyme . In muscle dystrophies, where the lack of DGC hampers the subsarcolemmal localization of nNOS, decreased nNOS gene expression reduces the sarcoplasmic accumulation of the enzyme , which, however, remains in sufficient amount to contribute to nitrosative stress and reduce muscle force .…”

Section: Introductionmentioning

confidence: 99%

“…Muscle atrophy induced by unloading can be significantly attenuated by interventions aimed to preserve the sarcolemmal localization of active nNOS, i.e. by affecting protein levels of the nNOS‐interacting chaperone Grp94/gp96 or by increasing the endogenous antioxidant defense .…”

Section: Introductionmentioning

confidence: 99%

“…In fact, T8 biopsies did not show myofiber atrophy . Nevertheless, all the samples were evaluated de novo using a fiber orientation‐independent parameter , and sarcolemmal nNOS activity was investigated using modified NADPH‐diaphorase (NADPH‐d) histochemistry . The experimental animal model of muscle disuse and simulated microgravity – the tail‐suspended rat – was then used to validate the results and to inhibit in vivo nNOS activity after short unloading periods, to provide mechanistic evidence of the participation of the active enzyme in atrophy initiation of unloaded myofibers.…”

Section: Introductionmentioning

confidence: 99%

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Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress‐dependent, early event driving disuse atrophy

Terradas

Vitadello

Traini

et al. 2018

The Journal of Pathology

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Skeletal muscle atrophy following unloading or immobilization represents a major invalidating event in bedridden patients. Among mechanisms involved in atrophy development, a controversial role is played by neuronal NOS (nNOS; NOS1), whose dysregulation at the protein level and/or subcellular distribution also characterizes other neuromuscular disorders. This study aimed to investigate unloading-induced changes in nNOS before any evidence of myofiber atrophy, using vastus lateralis biopsies obtained from young healthy subjects after a short bed-rest and rat soleus muscles after exposure to short unloading periods. Our results showed that (1) changes in nNOS subcellular distribution using NADPH-diaphorase histochemistry to detect enzyme activity were observed earlier than using immunofluorescence to visualize the protein; (2) loss of active nNOS from the physiological subsarcolemmal localization occurred before myofiber atrophy, i.e. in 8-day bed-rest biopsies and in 6 h-unloaded rat soleus, and was accompanied by increased nNOS activity in the sarcoplasm; (3) nNOS (Nos1) transcript and protein levels decreased significantly in the rat soleus after 6 h and 1 day unloading, respectively, to return to ambulatory levels after 4 and 7 days of unloading, respectively; (4) unloading-induced nNOS redistribution appeared dependent on mitochondrial-derived oxidant species, indirectly measured by tropomyosin disulfide bonds which had increased significantly in the rat soleus already after a 6 h-unloading bout; (5) activity of displaced nNOS molecules is required for translocation of the FoxO3 transcription factor to myofiber nuclei. FoxO3 nuclear localization in rat soleus increased after 6 h unloading (about four-fold the ambulatory level), whereas it did not when nNOS expression and activity were inhibited in vivo before and during 6 h unloading. In conclusion, this study demonstrates that the redistribution of active nNOS molecules from sarcolemma to sarcoplasm not only is ahead of the atrophy of unloaded myofibers, and is induced by increased production of mitochondrial superoxide anion, but also drives FoxO3 activation to initiate muscle atrophy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Loss of melusin is a novel, neuronal NO synthase/FoxO3‐independent master switch of unloading‐induced muscle atrophy

Vitadello

Sorge

Percivalle

et al. 2020

J cachexia sarcopenia muscle

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Background Unloading/disuse induces skeletal muscle atrophy in bedridden patients and aged people, who cannot prevent it by means of exercise. Because interventions against known atrophy initiators, such as oxidative stress and neuronal NO synthase (nNOS) redistribution, are only partially effective, we investigated the involvement of melusin, a muscle‐specific integrin‐associated protein and a recognized regulator of protein kinases and mechanotransduction in cardiomyocytes. Methods Muscle atrophy was induced in the rat soleus by tail suspension and in the human vastus lateralis by bed rest. Melusin expression was investigated at the protein and transcript level and after treatment of tail‐suspended rats with atrophy initiator inhibitors. Myofiber size, sarcolemmal nNOS activity, FoxO3 myonuclear localization, and myofiber carbonylation of the unloaded rat soleus were studied after in vivo melusin replacement by cDNA electroporation, and muscle force, myofiber size, and atrogene expression after adeno‐associated virus infection. In vivo interference of exogenous melusin with dominant‐negative kinases and other atrophy attenuators (Grp94 cDNA; 7‐nitroindazole) on size of unloaded rat myofibers was also explored. Results Unloading/disuse reduced muscle melusin protein levels to about 50%, already after 6 h in the tail‐suspended rat (P < 0.001), and to about 35% after 8 day bed rest in humans (P < 0.05). In the unloaded rat, melusin loss occurred despite of the maintenance of β1D integrin levels and was not abolished by treatments inhibiting mitochondrial oxidative stress, or nNOS activity and redistribution. Expression of exogenous melusin by cDNA transfection attenuated atrophy of 7 day unloaded rat myofibers (−31%), compared with controls (−48%, P = 0.001), without hampering the decrease in sarcolemmal nNOS activity and the increase in myonuclear FoxO3 and carbonylated myofibers. Infection with melusin‐expressing adeno‐associated virus ameliorated contractile properties of 7 day unloaded muscles (P ≤ 0.05) and relieved myofiber atrophy (−33%) by reducing Atrogin‐1 and MurF‐1 transcripts (P ≤ 0.002), despite of a two‐fold increase in FoxO3 protein levels (P = 0.03). Atrophy attenuation by exogenous melusin did not result from rescue of Akt, ERK, or focal adhesion kinase activity, because it persisted after co‐transfection with dominant‐negative kinase forms (P < 0.01). Conversely, melusin cDNA transfection, combined with 7‐nitroindazole treatment or with cDNA transfection of the nNOS‐interacting chaperone Grp94, abolished 7 day unloaded myofiber atrophy. Conclusions Disuse/unloading‐induced loss of melusin is an early event in muscle atrophy which occurs independently from mitochondrial oxidative stress, nNOS redistribution, and FoxO3 activation. Only preservation of melusin levels and sarcolemmal nNOS localization fully prevented muscle mass loss, demonstrating that both of them act as independent, but complementary, master switches of muscle disuse atrophy.

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The Stress Protein/Chaperone Grp94 Counteracts Muscle Disuse Atrophy by Stabilizing Subsarcolemmal Neuronal Nitric Oxide Synthase

Abstract: Maintenance of Grp94 expression is sufficient to counter unloading atrophy and oxidative stress by mechanistically stabilizing nNOS-multiprotein complex at the myofiber sarcolemma.

Cited by 25 publications

References 75 publications

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress‐dependent, early event driving disuse atrophy

Loss of melusin is a novel, neuronal NO synthase/FoxO3‐independent master switch of unloading‐induced muscle atrophy

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