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The Effect of Losartan on Skeletal Muscle Wasting in a Mouse Model of Cancer-Related Fatigue. Yvonne Clark, Runfeng Jing, Loren Wold, Donna McCarthy Beckett. Significance. 75-90% of patients with incurable cancer complain of fatigue and 41% describe their fatigue as severe.

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the effect of losartan on skeletal muscle wasting in a mouse model of cancer related fatigue

The Effect of Losartan on Skeletal Muscle Wasting in a Mouse Model of Cancer-Related Fatigue

Yvonne Clark, Runfeng Jing, Loren Wold, Donna McCarthy Beckett

significance
Significance
  • 75-90% of patients with incurable cancer complain of fatigue and 41% describe their fatigue as severe.
  • Cancer related fatigue (CRF) is more distressing than pain, nausea, or vomiting.
  • Symptoms of weakness and reduced effort tolerance often co-occur with CRF.
significance1
Significance

The causes of CRF are multimodal and not clearly understood. Several proposed mechanisms include

  • disturbances in HPA activity,
  • decreased serotonin synthesis,
  • altered circadian rhythms,
  • sleep disturbances
  • anemia
  • Increased serum levels of pro-inflammatory cytokines
  • loss of skeletal muscle mass
background
Background

Muscle mass is a balance between protein degradation and protein synthesis

Protein Degradation

MAFbx

BNIP3

Protein Synthesis

MyoD

IGF-1

Muscle Mass

background1
Background

Serum levels of pro-inflammatory cytokines, such as IL-6, are increased in patients with CRF and in mouse models of tumor-induced muscle wasting.

IL-6 increases muscle expression of biomarkers of metabolic pathways associated with muscle protein degradation.

  • MAFbx
  • BNIP3.
background2
Background

Patients with congestive heart failure, COPD, and renal disease also often have muscle wasting and fatigue and elevated serum levels of IL-6 and……. Angiotensin II.

Infusion of Angiotensin II increases serum IL-6, increases muscle expression of MAFbx and suppresses serum levels of IGF-1 causing muscle wasting in otherwise healthy animals.

angiotensin ii
Angiotensin II
  • Angiotensin II exerts most of its biological effects through binding AT1 or AT2 receptors.
  • The AT1 receptor blocker Losartanprevented skeletal muscle wasting in a mouse model of disuse atrophy.
purpose
Purpose

The purpose of this study was to determine if Losartan would reduce skeletal muscle wasting, symptoms of fatigue, and biomarkers of muscle metabolism in tumor bearing mice.

methodology
Methodology

In mice, fatigue is modeled as decreased voluntary wheel running activity (VWRA).

methodology1
Methodology

In mice, weakness is modeled as decreased grip strength.

methodology2
Methodology
  • Adult female mice were acclimated to the running wheels before being inoculated subcutaneously with C26 tumor cells.
  • One half of control and tumor bearing mice received Losartan 10mg/kg/day in their drinking water.
  • VWRA was monitored over the course of tumor growth.
  • Grip strength was measured before sacrifice .
methodology3
Methodology
  • Mice were euthanized on day 19 and the gastrocnemius muscles were removed and weighed. Muscles were homogenized in Trizol for extraction of total RNA.
  • Expression of IL-6, MAFbx, BNIP3, MyoD, and IGF-1 mRNA was determined using real-time PCR. Expression of each gene was normalized to mean expression of the house-keeping gene GAPDH.
methodology4
Methodology
  • Muscle mass is reported as grams muscle weight normalized to body weight.
  • Grip strength is reported as the average of 3 tests to determine grams of force needed to dislodge the mouse from the wire mesh normalized to body weight.
  • VWRA is reported as total wheel turns/24 hours.
  • Data was analyzed using two-way (tumor, drug) and repeated measures analysis of variance.
results gastroc muscle weight normalized to body weight
Results: Gastroc Muscle Weight(normalized to body weight)

* Tumor effect, p=.001

+ Drug effect, p<.05

Tumor-Drug interaction, p<.05

results muscle expression of il 6
Results: Muscle expression of IL-6

* Tumor effect, p<.001

+ Drug effect , p<.01

Tumor-Drug interaction, p<.05

results muscle expression of igf 1
Results: Muscle Expression of IGF-1

* Tumor effect, p=.01

+ Drug effect, p=.05

results vwra
Results: VWRA

Time factor, p<.001 (within subjects)

Tumor effect, p=.001 (between subjects)

Tumor-time interaction, p=.004

results grip strength
Results: Grip Strength

+ Drug effect, p=<.05

conclusion
Conclusion
  • VWRA progressively declined and skeletal muscle mass was significantly reduced in the tumor bearing mice.
  • Tumor growth significantly increased expression of IL-6, MAFbx, BNIP3 and IGF-1 mRNA in the gastrocnemius muscle, but did not affect expression of MyoD.
  • Treatment with 10mg/kg Losartan preserved muscle mass and grip strength in tumor bearing mice but did not affect VWRA in this mouse model of CRF.
conclusion1
Conclusion
  • Losartan reduced expression of IL-6 and IGF-1, but did not affect expression of MAFbx, BNIP3, or MyoD mRNA in the gastrocnemius muscle.
  • Because Losartan improved muscle mass and grip strength, but did not affect VWRA, we conclude that SMW may not be a major factor in the fatigue that occurs with incurable cancer.
  • The data also suggest that Losartan warrants further study in the treatment of tumor-induced SMW.