Targeted Overexpression of Mitochondrial Catalase Protects Against Cancer Chemotherapy-Induced Skeletal Muscle Dysfunction

Am J Physiol Endocrinol Metab. 2016 Aug 1;311(2):E293-301. doi: 10.1152/ajpendo.00540.2015. Epub 2016 Jun 21.

Abstract

The loss of strength in combination with constant fatigue is a burden on cancer patients undergoing chemotherapy. Doxorubicin, a standard chemotherapy drug used in the clinic, causes skeletal muscle dysfunction and increases mitochondrial H2O2 We hypothesized that the combined effect of cancer and chemotherapy in an immunocompetent breast cancer mouse model (E0771) would compromise skeletal muscle mitochondrial respiratory function, leading to an increase in H2O2-emitting potential and impaired muscle function. Here, we demonstrate that cancer chemotherapy decreases mitochondrial respiratory capacity supported with complex I (pyruvate/glutamate/malate) and complex II (succinate) substrates. Mitochondrial H2O2-emitting potential was altered in skeletal muscle, and global protein oxidation was elevated with cancer chemotherapy. Muscle contractile function was impaired following exposure to cancer chemotherapy. Genetically engineering the overexpression of catalase in mitochondria of muscle attenuated mitochondrial H2O2 emission and protein oxidation, preserving mitochondrial and whole muscle function despite cancer chemotherapy. These findings suggest mitochondrial oxidants as a mediator of cancer chemotherapy-induced skeletal muscle dysfunction.

Keywords: cancer; chemotherapy; mitochondria; reactive oxygen species; skeletal muscle.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy
  • Catalase / drug effects*
  • Catalase / genetics
  • Catalase / metabolism
  • Disease Models, Animal
  • Doxorubicin / pharmacology*
  • Electron Transport Complex I / drug effects
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / drug effects
  • Electron Transport Complex II / metabolism
  • Female
  • Hydrogen Peroxide / metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / drug effects*
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / metabolism
  • Muscle Contraction / drug effects
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / physiopathology
  • Oxidation-Reduction / drug effects
  • Proteins / drug effects
  • Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Proteins
  • Doxorubicin
  • Hydrogen Peroxide
  • Catalase
  • Electron Transport Complex II
  • Electron Transport Complex I