TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair

Ogura, Yuji; Hindi, Sajedah M.; Sato, Shuichi; Xiong, Guangyan; Akira, Shizuo; Kumar, Ashok

doi:10.1038/ncomms10123

Cited by 68 publications

(101 citation statements)

References 67 publications

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“…Literature shows that ERK signaling can be both stimulatory and inhibitory for muscle differentiation. ERK1/2 activation is necessary for satellite cell proliferation and self-renewal (Ogura et al, 2015; Hindi and Kumar, 2016), but not required for fusion or expression of muscle specific genes (Jones et al, 2001). In addition, ERK2 is necessary for myotube formation, as siRNA-mediated knockdown of ERK2 in C2C12 myoblasts inhibited their fusion into multinucleated myotubes (Li and Johnson, 2006).…”

Section: Discussionmentioning

confidence: 99%

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

Au¹,

Desai

Koniaris

et al. 2017

Front. Physiol.

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Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific.

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Section: Discussionmentioning

confidence: 99%

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

Au¹,

Desai

Koniaris

et al. 2017

Front. Physiol.

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“…We present the data as mean ± standard deviation (SD). We use paired or unpaired Student’s t -test to determine statistical differences among different groups similar to as described (Ogura et al , 2015; Hindi and Kumar, 2016). A P < 0.05 is considered as statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…In our laboratory, we have adapted and standardized a previously published protocol (Rando and Blau, 1994) for the isolation of myoblasts from skeletal muscle of adult mice. This protocol is highly efficient for the generation of a large amount of purified myoblasts from skeletal muscle of adult mice (Ogura et al , 2015; Hindi and Kumar, 2016). The purity of the myoblasts can be assayed by immunostaining of the cells for Pax7 and MyoD proteins which are expressed in undifferentiated myoblasts.…”

Section: Introductionmentioning

confidence: 99%

Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice

et al. 2017

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Myogenesis is a multi-step process that leads to the formation of skeletal muscle during embryonic development and repair of injured myofibers. In this process, myoblasts are the main effector cell type which fuse with each other or to injured myofibers leading to the formation of new myofibers or regeneration of skeletal muscle in adults. Many steps of myogenesis can be recapitulated through in vitro differentiation of myoblasts into myotubes. Most laboratories use immortalized myogenic cells lines that also differentiate into myotubes. Although these cell lines have been found quite useful to delineating the regulatory mechanisms of myogenesis, they often show a great degree of variability depending on the origin of the cells and culture conditions. Primary myoblasts have been suggested as the most physiologically relevant model for studying myogenesis in vitro. However, due to their low abundance in adult skeletal muscle, isolation of primary myoblasts is technically challenging. In this article, we describe an improved protocol for the isolation of primary myoblasts from adult skeletal muscle of mice. We also describe methods for their culturing and differentiation into myotubes.

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“…We present the data as mean ± standard deviation (SD). We used paired or unpaired Student's t -test to determine statistical differences among different groups similar to as described (Hindi and Kumar, 2016; Ogura et al ., 2015; Ogura et al ., 2013). A P < 0.05 is considered as statistically significant.…”

Section: Discussionmentioning

confidence: 99%

“…Representative individual anti-MyoD, anti-Pax7, DAPI stained and merged images generated using this protocol have been published in our recent publications (Hindi and Kumar, 2016; Ogura et al ., 2015). A representative image of staining of satellite cell cluster on myofibers after 72 h of culturing is presented in Figure 4.…”

Section: Methodsmentioning

confidence: 99%

Isolation, Culture, and Staining of Single Myofibers

Gallot¹,

Hindi²,

Mann³

et al. 2016

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Adult skeletal muscle regeneration is orchestrated by a specialized population of adult stem cells called satellite cells, which are localized between the basal lamina and the plasma membrane of myofibers. The process of satellite cell-activation, proliferation, and subsequent differentiation that occurs during muscle regeneration can be recapitulated ex vivo by isolation of single myofibers from skeletal muscles and culturing them under suspension conditions. Here, we describe an improved protocol to evaluate ex vivo satellite cells activation through isolation of single myofibers from extensor digitorum longus (EDL) muscle of mice and culturing and staining of myofiber-associated satellite cells with the markers of self-renewal, proliferation, and differentiation.

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TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair

Cited by 68 publications

References 67 publications

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice

Isolation, Culture, and Staining of Single Myofibers

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