scholarly journals Mitogen-Activated Protein Kinase-Dependent Fiber-Type Regulation in Skeletal Muscle

2018 ◽  
Author(s):  
Justin G. Boyer ◽  
Taejeong Song ◽  
Donghoon Lee ◽  
Xing Fu ◽  
Sakthivel Sadayappan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinases ◽  
Fiber Type ◽  
Mouse Genetics ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Specific Expression ◽  
Mitogen Activated Protein ◽  
Similar Phenotype

AbstractMitogen-activated protein kinases (MAPK) are conserved protein kinases that regulate a diverse array of cellular activities. Stress or mitogenic signals activate three primary branches of the greater MAPK cascade, each of which consists of a phosphorylation-dependent array of successively acting kinases. The extracellular signal-regulated kinase 1/2 (ERK1/2) branch is regulated by growth factory signaling at the cell membrane, leading to phosphorylation of the dual-specificity kinase MEK1, which is dedicated to ERK1/2 phosphorylation. Previous studies have established a link between MAPK activation and endurance exercise, but whether a single MAPK is responsible for establishing muscle metabolic fate is unclear. Using mouse genetics we observed that muscle-specific expression of a constitutively active MEK1 promotes greater ERK1/2 signaling that mediates fiber-type switching in mouse skeletal muscle to a slow, oxidative phenotype with type I myosin heavy chain expression. Induced expression of the activated MEK1 mutant using either a MyoD-Cre or myosin light chain-Cre strategy equally increased the number of type I fibers in skeletal muscle with significantly reduced size compared to controls. Moreover, activation of MEK1 in mature myofibers of an adult mouse using a transgene containing a tamoxifen inducible MerCreMer cDNA under the control of a skeletal α-actin promoter produced a similar phenotype of switching towards a slow-oxidative program. Physiologic assessment of mice with greater skeletal muscle slow-oxidative fibers showed enhanced metabolic activity and oxygen consumption with greater fatigue resistance of individual muscles. In summary, these results show that sustained MEK1-ERK1/2 activity in skeletal muscle produces a fast-to-slow fiber-type switch, suggesting that modulation of this signaling pathway may represent a therapeutic approach to enhance the long-term metabolic effectiveness of musclein vivo.

scholarly journals The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK

2006 ◽  
Vol 27 (1) ◽  
pp. 170-181 ◽  
Author(s):  
N. Ronkina ◽  
A. Kotlyarov ◽  
O. Dittrich-Breiholz ◽  
M. Kracht ◽  
E. Hitti ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Protein Kinases ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Double Knockout ◽  
Mitogen Activated Protein ◽  
Deficient Mice ◽  
Necrosis Factor

ABSTRACT MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

scholarly journals The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases

1999 ◽  
Vol 19 (2) ◽  
pp. 1569-1581 ◽  
Author(s):  
Cathy Tournier ◽  
Alan J. Whitmarsh ◽  
Julie Cavanagh ◽  
Tamera Barrett ◽  
Roger J. Davis
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Cultured Cells ◽  
Biochemical Properties ◽  
Mitogen Activated Protein Kinase ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Jnk Activation

ABSTRACT The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (α, β, and γ isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7α isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7α isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7β and MKK7γ isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that theMKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

Static stretch increases c-Jun NH2-terminal kinase activity and p38 phosphorylation in rat skeletal muscle

2001 ◽  
Vol 280 (2) ◽  
pp. C352-C358 ◽  
Author(s):  
Marni D. Boppart ◽  
Michael F. Hirshman ◽  
Kei Sakamoto ◽  
Roger A. Fielding ◽  
Laurie J. Goodyear
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Protein Kinases ◽  
Human Skeletal Muscle ◽  
Fiber Type ◽  
Eccentric Contractions ◽  
Sprague Dawley ◽  
Static Stretch

Physical exercise and contraction increase c-Jun NH2-terminal kinase (JNK) activity in rat and human skeletal muscle, and eccentric contractions activate JNK to a greater extent than concentric contractions in human skeletal muscle. Because eccentric contractions include a lengthening or stretch component, we compared the effects of isometric contraction and static stretch on JNK and p38, the stress-activated protein kinases. Soleus and extensor digitorum longus (EDL) muscles dissected from 50- to 90-g male Sprague-Dawley rats were subjected to 10 min of electrical stimulation that produced contractions and/or to 10 min of stretch (0.24 N tension, 20–25% increase in length) in vitro. In the soleus muscle, contraction resulted in a small, but significant, increase in JNK activity (1.8-fold above basal) and p38 phosphorylation (4-fold). Static stretch had a much more profound effect on the stress-activated protein kinases, increasing JNK activity 19-fold and p38 phosphorylation 21-fold. Increases in JNK activation and p38 phosphorylation in response to static stretch were fiber-type dependent, with greater increases occurring in the soleus than in the EDL. Immunohistochemistry performed with a phosphospecific antibody revealed that activation of JNK occurred within the muscle fibers. These studies suggest that the stretch component of a muscle contraction may be a major contributor to the increases in JNK activity and p38 phosphorylation observed after exercise in vivo.

scholarly journals p38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261

2016 ◽  
Vol 36 (10) ◽  
pp. 1540-1554 ◽  
Author(s):  
Jonah Beenstock ◽  
Dganit Melamed ◽  
Navit Mooshayef ◽  
Dafna Mordechay ◽  
Benjamin P. Garfinkel ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
Structural Element ◽  
Muscle Tissues ◽  
Mitogen Activated Protein ◽  
Loop Residue ◽  
Mapk Kinases

Many enzymes are self-regulated and can either inhibit or enhance their own catalytic activity. Enzymes that do both are extremely rare. Many protein kinases autoactivate by autophosphorylating specific sites at their activation loop and are inactivated by phosphatases. Although mitogen-activated protein kinases (MAPKs) are usually activated by dual phosphorylation catalyzed by MAPK kinases (MAPKKs), the MAPK p38β is exceptional and is capable of self-activation bycisautophosphorylation of its activation loop residue T180. We discovered that p38β also autophosphorylates intranstwo previously unknown sites residing within a MAPK-specific structural element known as the MAPK insert: T241 and S261. Whereas phosphorylation of T180 evokes catalytic activity, phosphorylation of S261 reduces the activity of T180-phosphorylated p38β, and phosphorylation of T241 reduces its autophosphorylation intrans. Both phosphorylations do not affect the activity of dually phosphorylated p38β. T241 of p38β is found phosphorylatedin vivoin bone and muscle tissues. In myogenic cell lines, phosphorylation of p38β residue T241 is correlated with differentiation to myotubes. T241 and S261 are also autophosphorylated in intrinsically active variants of p38α, but in this protein, they probably play a different role. We conclude that p38β is an unusual enzyme that automodulates its basal, MAPKK-independent activity by several autophosphorylation events, which enhance and suppress its catalytic activity.

AMPK activation is fiber type specific in human skeletal muscle: effects of exercise and short-term exercise training

2009 ◽  
Vol 107 (1) ◽  
pp. 283-289 ◽  
Author(s):  
Robert S. Lee-Young ◽  
Benedict J. Canny ◽  
Damian E. Myers ◽  
Glenn K. McConell
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Human Skeletal Muscle ◽  
Fiber Type ◽  
Type I ◽  
Specific Expression ◽  
Ampk Phosphorylation ◽  
Before And After ◽  
Subunit Expression ◽  
Exercise Induced

AMP-activated protein kinase (AMPK) has been extensively studied in whole muscle biopsy samples of humans, yet the fiber type-specific expression and/or activation of AMPK is unknown. We examined basal and exercise AMPK-α Thr172 phosphorylation and AMPK subunit expression (α1, α2, and γ3) in type I, IIa, and IIx fibers of human skeletal muscle before and after 10 days of exercise training. Before training basal AMPK phosphorylation was greatest in type IIa fibers ( P < 0.05 vs. type I and IIx), while an acute bout of exercise increased AMPK phosphorylation in all fibers ( P < 0.05), with the greatest increase occurring in type IIx fibers. Exercise training significantly increased basal AMPK phosphorylation in all fibers, and the exercise-induced increases were uniformly suppressed compared with pretraining exercise. Expression of AMPK-α1 and -α2 was similar between fibers and was not altered by exercise training. However, AMPK-γ3 was differentially expressed in skeletal muscle fibers (type IIx > type IIa > type I), irrespective of training status. Thus skeletal muscle AMPK phosphorylation and AMPK expression are fiber type specific in humans in the basal state, as well as during exercise. Our findings reveal fiber type-specific differences that have been masked in previous studies examining mixed muscle samples.

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2727-2735 ◽  
Author(s):  
Vanessa S. Cull ◽  
Peta A. Tilbrook ◽  
Emmalene J. Bartlett ◽  
Natalie L. Brekalo ◽  
Cassandra M. James
Keyword(s):  
Viral Infections ◽  
Mitogen Activated Protein Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Naked Dna ◽  
Stage Of Development ◽  
Mitogen Activated Protein ◽  
Individual Type

Type I interferons (IFNs), pleiotropic cytokines with antiviral, antiproliferative, apoptotic, and immunoregulatory functions, are efficacious in the treatment of malignancies, viral infections, and autoimmune diseases. Binding of these cytokines to their cognate receptor leads to activation of the Jak-signal transducers and activators of transcription (STAT) signaling pathway and altered gene expression. This signal pathway has been intensely studied using human IFN-α2 and IFN-β. However, there are over 14 human IFN-α subtypes and over 10 murine IFN-α subtypes, with a single IFN-β subtype in both species. J2E cells are immortalized at the proerythroblast stage of development and produce a rapid and fatal erythroleukemia in vivo. These cells retain the ability to respond to erythropoietin in vitro by proliferating, differentiating, and remaining viable in the absence of serum. Here, we show that J2E cells are also functionally regulated differentially by IFN subtype treatment in vitro. A novel finding was the selective activation of STAT and mitogen-activated protein kinase (MAPK) molecules by different subtypes binding the IFN receptor. These findings indicate distinct effects for individual type I IFN subtypes, which are able to differentially activate members of the STAT and MAPK family. Finally, we investigated the efficacy of IFN naked DNA therapy in treating J2E-induced erythroleukemia in athymic nude mice. IFN subtypes differentially regulated the onset of erythroleukemia with delayed onset and increased survival, possibly via a reduction in cell viability, and enhanced antiproliferative and apoptotic effects observed for IFNA6 and IFNA9treatment, respectively. Moreover, these data highlight the necessity to choose the best IFN subtype in disease treatment.

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

2008 ◽  
Vol 22 (8) ◽  
pp. 2990-3000 ◽  
Author(s):  
Hao Shi ◽  
Jason M. Scheffler ◽  
Jonathan M. Pleitner ◽  
Caiyun Zeng ◽  
Sungkwon Park ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Fiber ◽  
Fiber Type ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Type ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Signaling ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signaling

In vivo 31P-NMR spectroscopy of chronically stimulated canine skeletal muscle

1988 ◽  
Vol 254 (2) ◽  
pp. C258-C266 ◽  
Author(s):  
B. J. Clark ◽  
M. A. Acker ◽  
K. McCully ◽  
H. V. Subramanian ◽  
R. L. Hammond ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nmr Spectroscopy ◽  
Energy Demand ◽  
31P Nmr ◽  
Fiber Type ◽  
Isometric Tension ◽  
31P Nmr Spectroscopy ◽  
Type I ◽  
Control Muscle

Chronic stimulation converts skeletal muscle of mixed fiber type to a uniform muscle made up of type I, fatigue-resistant fibers. Here, the bioenergetic correlates of fatigue resistance in conditioned canine latissimus dorsi are assessed with in vivo phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy. After chronic electrical stimulation, five dogs underwent 31P-NMR spectroscopic and isometric tension measurements on conditioned and contralateral control muscle during stimulation for 200, 300, 500, and 800 ms of an 1,100-ms duty cycle. With stimulation, phosphocreatine (PCr) fell proportional to the degree of stimulation in both conditioned and control muscle but fell significantly less in conditioned muscle at all but the least intense stimulation period (200 ms). Isometric tension, expressed as a tension time index per gram muscle, was significantly greater in the conditioned muscle at the two longest stimulation periods. The overall small change in PCr and the lack of a plateau in tension observed in the conditioned muscle are similar to that seen in cardiac muscle during increased energy demand. This study indicates that the conditioned muscle's markedly enhanced resistance to fatigue is in part the result of its increased capacity for oxidative phosphorylation.

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