Diaphragm and ventilatory dysfunction during cancer cachexia

FASEB J. 2013 Jul;27(7):2600-10. doi: 10.1096/fj.12-222844. Epub 2013 Mar 20.


Cancer cachexia is characterized by a continuous loss of locomotor skeletal muscle mass, which causes profound muscle weakness. If this atrophy and weakness also occurs in diaphragm muscle, it could lead to respiratory failure, which is a major cause of death in patients with cancer. Thus, the purpose of the current study was to determine whether colon-26 (C-26) cancer cachexia causes diaphragm muscle fiber atrophy and weakness and compromises ventilation. All diaphragm muscle fiber types were significantly atrophied in C-26 mice compared to controls, and the atrophy-related genes, atrogin-1 and MuRF1, significantly increased. Maximum isometric specific force of diaphragm strips, absolute maximal calcium activated force, and maximal specific calcium-activated force of permeabilized diaphragm fibers were all significantly decreased in C-26 mice compared to controls. Further, isotonic contractile properties of the diaphragm were affected to an even greater extent than isometric function. Ventilation measurements demonstrated that C-26 mice have a significantly lower tidal volume compared to controls under basal conditions and, unlike control mice, an inability to increase breathing frequency, tidal volume, and, thus, minute ventilation in response to a respiratory challenge. These data demonstrate that C-26 cancer cachexia causes profound respiratory muscle atrophy and weakness and ventilatory dysfunction.

Keywords: C-26; limb muscle; muscle function; respiratory muscles; single fiber.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Blotting, Western
  • Cachexia / etiology
  • Cachexia / physiopathology*
  • Cell Line, Tumor
  • Colonic Neoplasms / complications
  • Colonic Neoplasms / physiopathology*
  • Diaphragm / metabolism
  • Diaphragm / pathology
  • Diaphragm / physiopathology*
  • Gene Expression
  • Immunohistochemistry
  • Mice
  • Muscle Proteins / genetics
  • Muscle Weakness / etiology
  • Muscle Weakness / physiopathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Atrophy / etiology
  • Muscular Atrophy / physiopathology*
  • Myosin Heavy Chains / metabolism
  • Respiratory Insufficiency / etiology
  • Respiratory Insufficiency / physiopathology*
  • Respiratory Muscles / metabolism
  • Respiratory Muscles / pathology
  • Respiratory Muscles / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • SKP Cullin F-Box Protein Ligases / genetics
  • Tripartite Motif Proteins
  • Tropomyosin / metabolism
  • Troponin / metabolism
  • Ubiquitin-Protein Ligases / genetics


  • Actins
  • Muscle Proteins
  • Tripartite Motif Proteins
  • Tropomyosin
  • Troponin
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Myosin Heavy Chains