Osteolytic breast cancer causes skeletal muscle weakness in an immunocompetent syngeneic mouse model

Jenna Regan, Carter Mikesell, Steven Reiken, Haifang Xu, Andrew R. Marks, Khalid Mohammad, Theresa Guise, David L. Waning

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Muscle weakness and cachexia are significant paraneoplastic syndromes of many advanced cancers. Osteolytic bone metastases are common in advanced breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients. Pathologic fracture caused by osteolytic cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture. Since muscle weakness is linked to risk of falls which are a major cause of fracture, we have investigated skeletal muscle response to OCIB. Here, we show that a syngeneic mouse model of OCIB (4T1 mammary tumor cells) leads to cachexia and skeletal muscle weakness associated with oxidation of the ryanodine receptor and calcium (Ca2+) release channel (RyR1). Muscle atrophy follows known pathways via both myostatin signaling and expression of muscle-specific ubiquitin ligases, atrogin-1 and MuRF1. We have identified a mechanism for skeletal muscle weakness due to increased oxidative stress on RyR1 via NAPDH oxidases [NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4)]. In addition, SMAD3 phosphorylation is higher in muscle from tumor-bearing mice, a critical step in the intracellular signaling pathway that transmits TGFβ signaling to the nucleus. This is the first time that skeletal muscle weakness has been described in a syngeneic model of OCIB and represents a unique model system in which to study cachexia and changes in skeletal muscle.

Original languageEnglish (US)
Article number358
JournalFrontiers in Endocrinology
Volume8
Issue numberDEC
DOIs
StatePublished - Dec 19 2017

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Muscle Weakness
Bone Neoplasms
Skeletal Muscle
Ryanodine Receptor Calcium Release Channel
Cachexia
Breast Neoplasms
NADPH Oxidase
Myostatin
Paraneoplastic Syndromes
Muscles
Spontaneous Fractures
Muscular Atrophy
Ligases
Ubiquitin
Neoplasms
Oxidoreductases
Oxidative Stress
Phosphorylation
Quality of Life
Neoplasm Metastasis

Keywords

  • Breast cancer
  • Immune competent
  • Muscle weakness
  • Osteolytic disease
  • Syngeneic tumor model

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Osteolytic breast cancer causes skeletal muscle weakness in an immunocompetent syngeneic mouse model. / Regan, Jenna; Mikesell, Carter; Reiken, Steven; Xu, Haifang; Marks, Andrew R.; Mohammad, Khalid; Guise, Theresa; Waning, David L.

In: Frontiers in Endocrinology, Vol. 8, No. DEC, 358, 19.12.2017.

Research output: Contribution to journalArticle

Regan, Jenna ; Mikesell, Carter ; Reiken, Steven ; Xu, Haifang ; Marks, Andrew R. ; Mohammad, Khalid ; Guise, Theresa ; Waning, David L. / Osteolytic breast cancer causes skeletal muscle weakness in an immunocompetent syngeneic mouse model. In: Frontiers in Endocrinology. 2017 ; Vol. 8, No. DEC.
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