scholarly journals Muscle RANK is a key regulator of Ca2+ storage, SERCA activity, and function of fast-twitch skeletal muscles

2016 ◽  
Vol 310 (8) ◽  
pp. C663-C672 ◽  
Author(s):  
Sébastien S. Dufresne ◽  
Nicolas A. Dumont ◽  
Antoine Boulanger-Piette ◽  
Val A. Fajardo ◽  
Daniel Gamu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Skeletal Muscle Function ◽  
Inotropic Effects ◽  
Plasmic Reticulum ◽  
Receptor Activator ◽  
Slow Twitch ◽  
And Function ◽  
Fast Twitch

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca2+ sensor, and altered activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) modulating Ca2+ storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca2+ storage and SERCA activity, ultimately affecting denervated skeletal muscle function.

scholarly journals HDAC2 regulates FoxO1 during RANKL-induced osteoclastogenesis

2016 ◽  
Vol 310 (10) ◽  
pp. C780-C787 ◽  
Author(s):  
Ce Dou ◽  
Nan Li ◽  
Ning Ding ◽  
Chuan Liu ◽  
Xiaochao Yang ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Bone Homeostasis ◽  
Akt Activation ◽  
Histone Deacetylase 2 ◽  
Forkhead Box ◽  
Receptor Activator ◽  
And Function

The bone-resorbing osteoclast (OC) is essential for bone homeostasis, yet deregulation of OCs contributes to diseases such as osteoporosis, osteopetrosis, and rheumatoid arthritis. Here we show that histone deacetylase 2 (HDAC2) is a key positive regulator during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Bone marrow macrophages (BMMs) showed increased HDAC2 expression during osteoclastogenesis. HDAC2 overexpression enhanced, whereas HDAC2 deletion suppressed osteoclastogenesis and bone resorption using lentivirus infection. Mechanistically, upon RANKL activation, HDAC2 activated Akt; Akt directly phosphorylates and abrogates Forkhead box protein O1 (FoxO1), which is a negative regulator during osteoclastogenesis through reducing reactive oxygen species. HDAC2 deletion in BMMs resulted in decreased Akt activation and increased FoxO1 activity during osteoclastogenesis. In conclusion, HDAC2 activates Akt thus suppresses FoxO1 transcription results in enhanced osteoclastogenesis. Our data imply the potential value of HDAC2 as a new target in regulating osteoclast differentiation and function.

scholarly journals Spi-C positively regulates RANKL-mediated osteoclast differentiation and function

2020 ◽  
Vol 52 (4) ◽  
pp. 691-701 ◽  
Author(s):  
Eun Mi Go ◽  
Ju Hee Oh ◽  
Jin Hee Park ◽  
Soo Young Lee ◽  
Na Kyung Lee
Keyword(s):  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Specific Domain ◽  
Receptor Activator ◽  
And Function

Abstract Spi-C is an SPI-group erythroblast transformation-specific domain transcription factor expressed during B-cell development. Here, we report that Spi-C is a novel receptor activator of nuclear factor-κB ligand (RANKL)-inducible protein that positively regulates RANKL-mediated osteoclast differentiation and function. Knockdown of Spi-C decreased the expression of RANKL-induced nuclear factor of activated T-cells, cytoplasmic 1, receptor activator of nuclear factor-κB (RANK), and tartrate-resistant acid phosphatase (TRAP), resulting in a marked decrease in the number of TRAP-positive multinucleated cells. Spi-C-transduced bone marrow-derived monocytes/macrophages (BMMs) displayed a significant increase in osteoclast formation in the presence of RANKL. In addition, Spi-C-depleted cells failed to show actin ring formation or bone resorption owing to a marked reduction in the expression of RANKL-mediated dendritic cell-specific transmembrane protein and the d2 isoform of vacuolar (H+) ATPase V0 domain, which are known osteoclast fusion-related genes. Interestingly, RANKL stimulation induced the translocation of Spi-C from the cytoplasm into the nucleus during osteoclastogenesis, which was specifically blocked by inhibitors of p38 mitogen-activated protein kinase (MAPK) or PI3 kinase. Moreover, Spi-C depletion prevented RANKL-induced MAPK activation and the degradation of inhibitor of κB-α (IκBα) in BMMs. Collectively, these results suggest that Spi-C is a novel positive regulator that promotes both osteoclast differentiation and function.

scholarly journals MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1α

2004 ◽  
Vol 200 (5) ◽  
pp. 601-611 ◽  
Author(s):  
Nobuaki Sato ◽  
Naoyuki Takahashi ◽  
Koji Suda ◽  
Midori Nakamura ◽  
Mariko Yamaki ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Myeloid Differentiation ◽  
Toll Like Receptor ◽  
Adaptor Molecule ◽  
Receptor Activator ◽  
And Function ◽  
Myeloid Differentiation Factor ◽  
Receptor Domain ◽  
Receptor Family

Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll–IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88−/−) mice and TRIF-deficient (TRIF−/−) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1α stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF−/− mice, but not MyD88−/− mice. These factors stimulated receptor activator of nuclear factor-κB ligand mRNA expression in TRIF−/− osteoblasts, but not MyD88−/− osteoblasts. LPS stimulated IL-6 production in TRIF−/− osteoblasts, but not TRIF−/− macrophages. LPS and IL-1α enhanced the survival of TRIF−/− osteoclasts, but not MyD88−/− osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MyD88−/− mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover.

Studies of the halothane-cooling contractures of skeletal muscle

1987 ◽  
Vol 65 (4) ◽  
pp. 697-703 ◽  
Author(s):  
Roberto T. Sudo ◽  
Gisele Zapata ◽  
Guilherme Suarez-Kurtz
Keyword(s):  
Skeletal Muscle ◽  
Synergistic Effects ◽  
Rabbit Muscle ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Dose Dependent ◽  
Muscle Biopsies ◽  
Ca Homeostasis ◽  
Potential Use

The characteristics of transient contractures elicited by rapid cooling of frog or mouse muscles perfused in vitro with solutions equilibrated with 0.5–2.0% halothane are reviewed. The data indicate that these halothane-cooling contractures are dose dependent and reproducible, and their amplitude is larger in muscles containing predominantly slow-twitch type fibers, such as the mouse soleus, than in muscles in which fast-twitch fibers predominate, such as the mouse extensor digitorum longus. The halothane-cooling contractures are potentiated in muscles exposed to succinylcholine. The effects of Ca2+-free solutions, of the local anesthetics procaine, procainamide, and lidocaine, and of the muscle relaxant dantrolene on the halothane-cooling contractures are consistent with the proposal that the halothane-cooling contractures result from synergistic effects of halothane and low temperature on Ca sequestration by the sarcoplasmic reticulum. Preliminary results from skinned rabbit muscle fibers support this proposal. The halothane concentrations required for the halothane-cooling contractures of isolated frog or mouse muscles are comparable with those observed in serum of patients during general anesthesia. Accordingly, fascicles dissected from muscle biopsies of patients under halothane anesthesia for programmed surgery develop large contractures when rapidly cooled. The amplitude of these halothane-cooling contractures declined with the time of perfusion of the muscle fascicles in vitro with halothane-free physiological solutions. It is suggested that the halothane-cooling contractures could be used as a simple experimental model for the investigation of the effects of halothane on Ca homeostasis and contractility in skeletal muscle and for study of drugs of potential use in the management of the contractures associated with the halothane-induced malignant hyperthermia syndrome. It is shown that salicylates, but not indomethacin or mefenamic acid, inhibit the halothane-cooling contractures.

scholarly journals The Functional Role of Calcineurin in Hypertrophy, Regeneration, and Disorders of Skeletal Muscle

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Kunihiro Sakuma ◽  
Akihiko Yamaguchi
Keyword(s):  
Skeletal Muscle ◽  
Functional Role ◽  
Muscular Hypertrophy ◽  
Growth And Remodeling ◽  
Muscular Disorders ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Calcineurin Activity ◽  
Muscle Remodeling

Skeletal muscle uses calcium as a second messenger to respond and adapt to environmental stimuli. Elevations in intracellular calcium levels activate calcineurin, a serine/threonine phosphatase, resulting in the expression of a set of genes involved in the maintenance, growth, and remodeling of skeletal muscle. In this review, we discuss the effects of calcineurin activity on hypertrophy, regeneration, and disorders of skeletal muscle. Calcineurin is a potent regulator of muscle remodeling, enhancing the differentiation through upregulation of myogenin or MEF2A and downregulation of the Id1 family and myostatin. Foxo may also be a downstream candidate for a calcineurin signaling molecule during muscle regeneration. The strategy of controlling the amount of calcineurin may be effective for the treatment of muscular disorders such as DMD, UCMD, and LGMD. Activation of calcineurin produces muscular hypertrophy of the slow-twitch soleus muscle but not fast-twitch muscles.

Glutamine synthetase induction by glucocorticoids is preserved in skeletal muscle of aged rats

1996 ◽  
Vol 271 (6) ◽  
pp. E1061-E1066 ◽  
Author(s):  
D. Meynial-Denis ◽  
M. Mignon ◽  
A. Miri ◽  
J. Imbert ◽  
E. Aurousseau ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glutamine Synthetase ◽  
Skeletal Muscles ◽  
Female Rats ◽  
Mrna Levels ◽  
Aged Rats ◽  
Adult Rats ◽  
Adult Age ◽  
Slow Twitch ◽  
Fast Twitch

Glutamine synthetase (GS) is a glucocorticoid-inducible enzyme that has a key role for glutamine synthesis in muscle. We hypothesized that the glucocorticoid induction of GS could be altered in aged rats, because alterations in the responsiveness of some genes to glucocorticoids were reported in aging. We compared the glucocorticoid-induced GS in fast-twitch and slow-twitch skeletal muscles (tibialis anterior and soleus, respectively) and heart from adult (age 6-8 mo) and aged (age 22 mo) female rats. All animals received dexamethasone (Dex) in their drinking water (0.77 +/- 0.10 and 0.80 +/- 0.08 mg/day per adult and aged rat, respectively) for 5 days. Dex caused an increase in both GS activity and GS mRNA in fast-twitch and slow-twitch skeletal muscles from adult and aged rats. In contrast, Dex increased GS activity in heart of adult rats, without any concomitant change in GS mRNA levels. Furthermore, Dex did not affect GS activity in aged heart. Thus the responsiveness of GS to an excess of glucocorticoids is preserved in skeletal muscle but not in heart from aged animals.

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