Hydrogen peroxide as a signal for skeletal muscle adaptations to exercise: What do concentrations tell us about potential mechanisms?

Abstract

Hydrogen peroxide appears to be the key reactive oxygen species involved in redox signalling, but comparisons of the low concentrations of hydrogen peroxide that are calculated to exist within cells with those previously shown to activate common signalling events in vitro indicate that direct oxidation of key thiol groups on "redox-sensitive" signalling proteins is unlikely to occur. A number of potential mechanisms have been proposed to explain how cells overcome this block to hydrogen peroxide-stimulated redox signalling and these will be discussed in the context of the redox-stimulation of specific adaptations of skeletal muscle to contractile activity and exercise. It is argued that current data implicate a role for currently unidentified effector molecules (likely to be highly reactive peroxidases) in propagation of the redox signal from sites of hydrogen peroxide generation to common adaptive signalling pathways.

Fig. 1

Schematic representation of the 2 potential routes by which H₂O₂ generated in contracting muscle fibres may activate key cell signalling pathways. (A) Generation of H₂O₂ by NADPH oxidase 2 on the plasma or T-tubule membrane occurs initially on the outside of the membrane but generates a substantial local increase in H₂O₂ concentration on both sides of the membrane that is sufficient to directly oxidise, so-called, “redox-sensitive” signalling proteins in key pathways. (B) Local generation of H₂O₂ is insufficient to directly oxidise the “redox-sensitive” signalling proteins in key pathways, but can react with highly sensitive peroxidases (e.g. Prx or Trx) which then further oxidise less sensitive proteins by disulphide exchange leading to indirect activation of the signalling pathways.