Distinct α2 Na,K-ATPase membrane pools are differently involved in early skeletal muscle remodeling during disuse

Кравцова, В. В.; Petrov, Alexey M.; Matchkov, Vladimir V.; Bouzinova, Elena V.; Vasiliev, A. N.; Benziane, Boubacar; Зефиров, А. Л.; Chibalin, Alexander V.; Heiny, Judith A.; Кривой, И. И.

doi:10.1085/jgp.201511494

Cited by 49 publications

(77 citation statements)

References 61 publications

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“…Although both nNOS and melusin are costamere proteins, unloading‐induced, mitochondrial‐derived oxidative stress initiates nNOS redistribution in the sarcoplasm, whereas it does not appear involved in melusin protein decrease. A short unloading bout induces also disorganization in the lipid‐ordered phase of sarcolemma, detachment of cytoskeletal components, such as the non‐muscle α‐actinin isoform 4, and loss of function of α 2 Na‐K‐ATPase pump . It remains to be determined whether any of these unloading‐induced perturbations would act upstream or downstream melusin loss from costameres and catabolism.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…These data suggest that PGC-1α expression in rat soleus muscle during the initial stage of unloading (24 h) is not regulated by AMPK activity and therefore cannot influence an expression pattern of MyHC isoforms. It is also possible that AMPK dephosphorylation may participate in other events during the early period of mechanical unloading: paradoxical increase in ribosomal protein S6 kinase (p70S6K) phosphorylation (Mirzoev et al 2016) or inactivation of the α2 subunit of Na + ,K + -ATPase (Kravtsova et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Rapid decline in MyHC I(β) mRNA expression in rat soleus during hindlimb unloading is associated with AMPK dephosphorylation

Vilchinskaya

Mochalova

Nemirovskaya

et al. 2017

The Journal of Physiology

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One of the key events that occurs during skeletal muscle inactivation is a change in myosin phenotype, i.e. increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC). It is known that calcineurin/nuclear factor of activated T-cells and AMP-activated protein kinase (AMPK) can regulate the expression of genes encoding MyHC slow isoform. Earlier, we found a significant decrease in phosphorylated AMPK in rat soleus after 24 h of hindlimb unloading (HU). We hypothesized that a decrease in AMPK phosphorylation and subsequent histone deacetylase (HDAC) nuclear translocation can be one of the triggering events leading to a reduced expression of slow MyHC. To test this hypothesis, Wistar rats were treated with AMPK activator (AICAR) for 6 days before HU as well as during 24 h of HU. We discovered that AICAR treatment prevented a decrease in pre-mRNA and mRNA expression of MyHC I as well as MyHC IIa mRNA expression. Twenty-four hours of hindlimb suspension resulted in HDAC4 accumulation in the nuclei of rat soleus but AICAR pretreatment prevented this accumulation. The results of the study indicate that AMPK dephosphorylation after 24 h of HU had a significant impact on the MyHC I and MyHC IIa mRNA expression in rat soleus. AMPK dephosphorylation also contributed to HDAC4 translocation to the nuclei of soleus muscle fibres, suggesting an important role of HDAC4 as an epigenetic regulator in the process of myosin phenotype transformation.

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“…Moreover, it is established that the α2 Na,K‐ATPase isozyme is enriched in endplate membrane where it co‐localizes and functionally and molecularly interacts with the nAChRs (Chibalin et al, ; Heiny et al, ; Matchkov & Krivoi, ). The loss of α2 Na,K‐ATPase activity accompanied by disturbances in lipid rafts are observed even after 6–12 hr of hindlimb suspension (Kravtsova et al, ; Petrov et al, ) suggesting the possibility of corresponding changes in the nAChRs distribution. Notably, in skeletal muscle, Na,K‐ATPase activation depends on adenosine monophosphate‐activated protein kinase (AMPK) (Benziane et al, ), a key regulator of glucose, lipid, and protein metabolism (Hardie, Schaffer, & Brunet, ).…”

Section: Introductionmentioning

confidence: 99%

Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension

Chibalin

Benziane

Zakyrjanova

et al. 2018

Journal Cellular Physiology

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Motor endplates naturally undergo continual morphological changes that are altered in response to changes in neuromuscular activity. This study examines the consequences of acute (6-12 hr) disuse following hindlimb suspension on rat soleus muscle endplate structural stability. We identify early changes in several key signaling events including markers of protein kinase activation, AMPK phosphorylation and autophagy markers which may play a role in endplate remodeling. Acute disuse does not change endplate fragmentation, however, it decreases both the individual fragments and the total endplate area. This decrease was accompanied by an increase in the mean fluorescence intensity from the nicotinic acetylcholine receptors which compensate the endplate area loss. Muscle disuse decreased phosphorylation of AMPK and its substrate ACC, and stimulated mTOR controlled protein synthesis pathway and stimulated autophagy. Our findings provide evidence that changes in endplate stability are accompanied by reduced AMPK phosphorylation and an increase in autophagy markers, and these changes are evident within hours of onset of skeletal muscle disuse.

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Distinct α2 Na,K-ATPase membrane pools are differently involved in early skeletal muscle remodeling during disuse

Abstract: Location, location, location. The Na-K pump of skeletal muscle is regulated differently at neuromuscular junctions.

Cited by 49 publications

References 61 publications

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

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

Rapid decline in MyHC I(β) mRNA expression in rat soleus during hindlimb unloading is associated with AMPK dephosphorylation

Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension

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