Dataset Information

The Effect of Estradiol Administration on Muscle Mass Loss and Cachexia Progression in Female Apc ^Min/+ Mice.

ABSTRACT: Cancer cachexia is a multifactorial muscle wasting condition characterized by severe body weight and muscle mass loss which is secondary to chronic disease. The mechanistic examination of cachexia has predominately focused on the male phenotype and created significant gaps in understanding cachexia progression in the female. Female hypogonadism can accompany cancer cachexia and is characterized by reduced circulating 17ß-estradiol and uterine atrophy. Estrogen has known functions in skeletal muscle homeostasis involving the regulation of muscle protein turnover, cellular stressors, and oxidative metabolism. However, 17ß-estradiol's ability to regulate cachexia progression in the female is not known. The purpose of this study was to determine the effect of gonadal function and estradiol administration on muscle mass loss and cachexia progression in female Apc ^Min/+ mice. Methods: Female C57BL/6 (B6; N = 82) and Apc ^Min/+ (MIN; N = 88) mice were used in two separate experiments. In experiment 1, mice were sacrificed at either 12 (N = 20) or 20 (N = 41) weeks of age. Body weight and estrous cycle presence was determined weekly. In experiment 2, B6 and MIN mice were randomly allocated to: Control (N = 17), received E2 pellet (E2, N = 18), ovariectomy surgery (OVX; N = 19) or ovariectomy surgery with E2 pellet (OVX + E2; N = 21). 17ß-estradiol was administered through an implanted slow-releasing pellet (0.1 mg). In estrogen and ovariectomy experiments, food intake, and functional outcomes were recorded 1 week prior to sacrifice. Results: We report that E2 administration prevented body weight loss, muscle mass loss, cage inactivity, and grip strength loss associated with cachexia. In skeletal muscle, E2 reduced skeletal muscle AMPK phosphorylation, improved mTORC1 signaling, and prevented mitochondrial dysfunction. Conclusion: Our results demonstrate a role for 17ß-estradiol for the prevention of skeletal muscle mass loss in female tumor bearing mice. Furthermore, 17ß-estradiol prevented cachexia's disruption in skeletal muscle signaling involving AMPK and mTORC1, in addition to improving mitochondrial function in female tumor bearing mice.

SUBMITTER: Counts BR

PROVIDER: S-EPMC6838005 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Effect of Estradiol Administration on Muscle Mass Loss and Cachexia Progression in Female Apc Min/+ Mice.

Counts Brittany R BR Fix Dennis K DK Hetzler Kimbell L KL Carson James A JA

Frontiers in endocrinology 20191101

Cancer cachexia is a multifactorial muscle wasting condition characterized by severe body weight and muscle mass loss which is secondary to chronic disease. The mechanistic examination of cachexia has predominately focused on the male phenotype and created significant gaps in understanding cachexia progression in the female. Female hypogonadism can accompany cancer cachexia and is characterized by reduced circulating 17ß-estradiol and uterine atrophy. Estrogen has known functions in skeletal mus ...[more]

PMID: 31736871

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Project description:Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.

Project description:A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP-/- cancer cell lines.

Dataset Information

The Effect of Estradiol Administration on Muscle Mass Loss and Cachexia Progression in Female Apc ^Min/+ Mice.

Publications

The Effect of Estradiol Administration on Muscle Mass Loss and Cachexia Progression in Female <i>Apc</i> <sup><i>Min</i>/+</sup> Mice.

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