Oxaliplatin induces muscle loss and muscle-specific molecular changes in Mice

Muscle Nerve. 2018 Apr;57(4):650-658. doi: 10.1002/mus.25966. Epub 2017 Oct 6.

Abstract

Introduction: Muscle wasting is a frequent, debilitating complication of cancer. The impact of colorectal cancer chemotherapeutic oxaliplatin on the development of muscle loss and associated molecular changes is of clinical importance.

Methods: C57BL/6J male mice were treated with oxaliplatin. Total body weights were measured and behavioral studies performed. Hindlimb muscle weights (gastrocnemius and soleus) were recorded in conjunction with gene and protein expression analysis.

Results: Oxaliplatin-treated mice displayed reduced weight gain and behavioral deficits. Mice treated over a shorter course had significantly increased STAT3 phosphorylation in gastrocnemius muscles. Mice receiving extended oxaliplatin treatment demonstrated reduced hindlimb muscle mass with upregulation of myopathy-associated genes Foxo3, MAFbx, and Bnip3.

Discussion: The findings suggest that oxaliplatin treatment can directly disrupt skeletal muscle homeostasis and promote muscle loss, which may be clinically relevant in the context of targeting fatigue and weakness in cancer patients. Muscle Nerve 57: 650-658, 2018.

Keywords: cancer; fatigue; muscle; oxaliplatin; survivorship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Body Weight / drug effects
  • Forkhead Box Protein O3 / drug effects
  • Forkhead Box Protein O3 / genetics
  • Gene Expression / drug effects*
  • Hindlimb
  • Male
  • Membrane Proteins / drug effects
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / drug effects
  • Mitochondrial Proteins / genetics
  • Muscle Proteins / drug effects
  • Muscle Proteins / genetics
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Organ Size / drug effects
  • Oxaliplatin / pharmacology*
  • SKP Cullin F-Box Protein Ligases / drug effects
  • SKP Cullin F-Box Protein Ligases / genetics
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism

Substances

  • Antineoplastic Agents
  • BNip3 protein, mouse
  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • Membrane Proteins
  • Mitochondrial Proteins
  • Muscle Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Oxaliplatin
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases