Indiana University-Purdue University Indianapolis (IUPUI) / The ability to preserve, protect, or grow skeletal muscle would greatly
benefit patients in health and disease. Understanding the molecular pathways
that regulate muscle size is necessary to develop interventions. The extracellular
signal-related kinase (ERK) and Hedgehog signaling pathways each play
necessary roles in skeletal muscle development. The ERK pathway has been
shown to both stimulate and inhibit muscle development at different stages, while
Hedgehog signaling is vital for embryonic muscle development. Thus, these
pathways represent prime targets for manipulation in diseases associated with
muscle loss.
In prior studies, cancer patients treated with the ERK inhibitor,
Selumetinib, experienced significant gains in lean body mass. To study the
mechanisms responsible, we tested the potential of Selumetinib to protect
against muscle wasting in muscle cell cultures and in mice with experimental
lung cancer. Selumetinib was able to induce hypertrophy of cultured muscle
cells. In mice, we observed a reduction in tumor mass and in circulating
mediators of muscle wasting including inflammatory cytokines. However,
Selumetinib treatment did not prevent cancer-induced muscle loss. Together,
these data suggest a diversity in the underlying molecular mechanisms and the need for careful consideration when extrapolating results across different disease
states, clinical trials, and model systems.
In separate studies, we found that the Hedgehog pathway was increased
in mice and patients with cancer-associated muscle wasting and inflammation. In
a series of studies in muscle cell cultures, in genetically modified mice, and in
mice bearing tumors, we found that inflammatory cytokines activated Hedgehog
expression in muscle. Hedgehog signaling promoted the replication of muscle
stem cells but reduced the expression of genes that specify mature muscle.
Inhibiting Hedgehog signaling promoted muscle growth, while activating it caused
muscle wasting. Furthermore, we identified unique properties of two proteins
activated by Hedgehog, Gli1 and Gli2, where Gli1 appears to promote muscle
stem cell proliferation and Gli2 mature muscle gene expression. These data
implicate the Hedgehog pathway, GLI1 and GLI2 as targets for treatment of
muscle wasting diseases. / 2 years
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/16276 |
| Date | 18 December 2017 |
| Creators | Au, Ernie Dennis |
| Contributors | Zimmers, Teresa A. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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