Myostatin Augments Muscle-Specific Ring Finger Protein-1 Expression Through an NF-kB Independent Mechanism in SMAD3 Null Muscle

Sriram, Sandhya; Subramanian, Savitha; Juvvuna, Prasanna Kumar; Ge, Xiaohu; Lokireddy, Sudarsanareddy; McFarlane, Craig; Wahli, Walter; Kambadur, Ravi; Sharma, Mridula

doi:10.1210/me.2013-1179

Cited by 41 publications

(32 citation statements)

References 48 publications

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“…It has been reported that excessive reactive oxygen species lead to upregulation of MuRF‐1 transcription in C2C12 cells (Sriram et al . ). Hydrogen peroxide also stimulated ubiquitin‐conjugating activity and expressions of atrogin‐1 and MuRF‐1 in C2C12 cells (Li et al .…”

Section: Discussionmentioning

confidence: 97%

Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle

Kadoguchi

Kinugawa

Takada

et al. 2015

Experimental Physiology

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New findings r What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? r What is the main finding and its importance?Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases.Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg −1 min −1 ) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure.

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Section: Discussionmentioning

confidence: 97%

Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle

Kadoguchi

Kinugawa

Takada

et al. 2015

Experimental Physiology

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“…While we confirmed that atrogin1 and UBR2 up‐regulation by activin A was mediated by p38β MAPK but not Akt, we also showed that MuRF1 up‐regulation by activin A was dependent on neither p38 MAPK nor Akt. Sriram et al showed previously that MuRF1 is up‐regulated by ActRIIB agonist myostatin independent of Smad3 or NF‐kB . Thus, up‐regulation of MuRF1 by activin A may be mediated by an unknown mechanism.…”

Section: Discussionmentioning

confidence: 97%

“…This led to a popular belief that the Smad2/3 signalling pathway is responsible for ActRIIB‐mediated muscle catabolism . However, recent data revealed that Smad3 knockout in mice does not spare the mice from muscle atrophy induced by the ActRIIB agonist myostatin, suggesting that Smad2/3 signalling is non‐essential for ActRIIB‐mediated muscle catabolism. As a member of the TGFβ receptor superfamily, ActRIIB activation in muscle cells leads to activation of TAK‐1, a kinase that activates a cascade of kinases resulting in the activation of p38 MAPK .…”

Section: Introductionmentioning

confidence: 99%

Activin A induces skeletal muscle catabolism via p38β mitogen‐activated protein kinase

Ding

Zhang

Sin

et al. 2016

J cachexia sarcopenia muscle

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BackgroundActivation of type IIB activin receptor (ActRIIB) in skeletal muscle leads to muscle atrophy because of increased muscle protein degradation. However, the intracellular signalling mechanism that mediates ActRIIB‐activated muscle catabolism is poorly defined.MethodsWe investigated the role of p38β mitogen‐activated protein kinases (MAPK) in mediating ActRIIB ligand activin A‐activated muscle catabolic pathways in C2C12 myotubes and in mice with perturbation of this kinase pharmacologically and genetically.ResultsTreatment of C2C12 myotubes with activin A or myostatin rapidly activated p38 MAPK and its effector C/EBPβ within 1 h. Paradoxically, Akt was activated at the same time through a p38 MAPK‐independent mechanism. These events were followed by up‐regulation of ubiquitin ligases atrogin1 (MAFbx) and UBR2 (E3α‐II), as well as increase in LC3‐II, a marker of autophagosome formation, leading to myofibrillar protein loss and myotube atrophy. The catabolic effects of activin A were abolished by p38α/β MAPK inhibitor SB202190. Using small interfering RNA‐mediated gene knockdown, we found that the catabolic activity of activin A was dependent on p38β MAPK specifically. Importantly, systemic administration of activin A to mice similarly activated the catabolic pathways in vivo, and this effect was blocked by SB202190. Further, activin A failed to activate the catabolic pathways in mice with muscle‐specific knockout of p38β MAPK. Interestingly, activin A up‐regulated MuRF1 in a p38 MAPK‐independent manner, and MuRF1 did not appear responsible for activin A‐induced myosin heavy chain loss and muscle atrophy.ConclusionsActRIIB‐mediated activation of muscle catabolism is dependent on p38β MAPK‐activated signalling.

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“…Thus, ROS produced as a result of oxidative stress contribute to development of muscle wasting, which occurs as a result of increased levels of muscle-specifi c ubiquitin ligases. A recent report showed that defi ciency of the smad3 gene, which is a downstream signaling molecule for TGF-␤ and myostatin, resulted in myostatin-induced ROS induction through the p38 and ERK MAPK pathways in skeletal muscle, leading to muscle atrophy (25). Given the importance of ROS in the development and cause of muscle proteolysis, inhibition of the MAPK-ROS signaling pathway by antioxidants and related nutrients may be critical for the development of new therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice

Hirasaka

Saito

Yamaguchi

et al. 2016

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Summary Proinfl ammatory cytokines contribute to the progression of muscle wasting caused by ubiquitin-proteasome-dependent proteolysis. We have previously demonstrated that isofl avones, such as genistein and daidzein, prevent TNF-␣-induced muscle atrophy in C2C12 myotubes. In this study, we examined the effect of dietary fl avonoids on the wasting of muscle. Mice were divided into the following four groups: vehicle-injected (control) mice fed the normal diet (CN); tumor-bearing mice fed the normal diet (TN); control mice fed the isofl avone diet (CI); and tumor-bearing mice fed the isofl avone diet (TI). There were no significant differences in the intake of food or body weight gain among these four groups. The wet weight and myofi ber size of gastrocnemius muscle in TN signifi cantly decreased, compared with those in CN. Interestingly, the wet weight and myofi ber size of gastrocnemius muscle in TI were nearly the same as those in CN and CI, although isofl avone supplementation did not affect the increased tumor mass or concentrations of proinfl ammatory cytokines, such as TNF-␣ and IL-6, in the blood. Moreover, increased expression of muscle-specifi c ubiquitin ligase genes encoding MAFbx/Atrogin-1 and MuRF1 in the skeletal muscle of TN was signifi cantly inhibited by the supplementation of isofl avones. In parallel with the expression of muscle-specifi c ubiquitin ligases, dietary isofl avones signifi cantly suppressed phosphorylation of ERK in tumor-bearing mice. These results suggest that dietary isofl avones improve muscle wasting in tumor-bearing mice via the ERK signaling pathway mediated-suppression of ubiquitin ligases in muscle cells.

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Myostatin Augments Muscle-Specific Ring Finger Protein-1 Expression Through an NF-kB Independent Mechanism in SMAD3 Null Muscle

Cited by 41 publications

References 48 publications

Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle

Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle

Activin A induces skeletal muscle catabolism via p38β mitogen‐activated protein kinase

Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice

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