Modifications of skeletal muscle ryanodine receptor type 1 and exercise intolerance in heart failure

J Heart Lung Transplant. 2013 Sep;32(9):925-9. doi: 10.1016/j.healun.2013.06.026.


Background: In experimental heart failure animal models, remodeling of skeletal and cardiac muscle ryanodine receptors (RyR), including phosphorylation, S-nitrosylation and oxidation, have been reported to contribute to pathologic Ca2+ release, impaired muscle function and fatigue. However, it is not known whether similar remodeling of RyR1 in skeletal muscle occurs in patients with heart failure, and if this is associated with impairment of physical activity.

Methods: We studied 8 sedentary patients with New York Heart Association (NYHA) Class III heart failure and 7 age-matched, healthy, but sedentary controls. All heart failure patients had NYHA Class III and peak VO2, echocardiography and NT-proBNP data consistent with moderate to severe heart failure. The age-matched controls included were allowed hypertension but sub-clinical heart failure was to have been ruled out by normal peak VO2, echocardiography and NT-proBNP.

Results: Exercise capacity (VO2max) differed by almost 2-fold between heart failure patients and age-matched controls. Compared with controls, skeletal muscle RyR1 in heart failure patients was excessively phosphorylated, S-nitrosylated and oxidized. Furthermore, RyR1 from heart failure patients was depleted of its stabilizing protein FK 506-binding protein 12 (FKBP12, or calstabin1).

Conclusions: For the first time we show that skeletal muscle RyR1 from human heart failure is post-translationally modified, which corroborates previous data from experimental animal studies. This indicates pathologic Ca2+ release as a potential mechanism behind skeletal muscle weakness and impaired exercise tolerance in patients with heart failure and suggests a potential target for pharmacologic intervention.

Keywords: ageing; muscle fatigue activity; physical exercise capacity calcium oxidative stress; post-translational contraction; protein processing.

Publication types

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

MeSH terms

  • Aged
  • Biopsy
  • Case-Control Studies
  • Comorbidity
  • Echocardiography
  • Exercise Tolerance / physiology*
  • Female
  • Heart Failure / epidemiology
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology*
  • Humans
  • Hypertension / epidemiology
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Natriuretic Peptide, Brain / metabolism
  • Oxygen Consumption / physiology
  • Peptide Fragments / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Severity of Illness Index


  • Peptide Fragments
  • Ryanodine Receptor Calcium Release Channel
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain