Modifications of the Skeletal Muscle Ryanodine Receptor Type 1 and Exercise Intolerance in Heart Failure

Abstract

PurposeContraction of both cardiac and skeletal myocytes is dependent on cytoplasmic Ca2+. During muscle contraction, Ca2+ is released from the sarcoplasmic reticulum through a Ca2+ release channel, the ryanodine receptor, RyR. In heart failure, adrenergic stimulation leads to posttranslational modifications of cardiac muscle RyR (RyR2), resulting in pathological Ca2+ leak and impaired contractility. If similar remodeling of skeletal muscle RyR1 occurs in heart failure patients, and if this is associated with further impairment of physical capacity and activity is unknown.Methods and MaterialsWe studied 8 sedentary patients with New York Heart Association (NYHA) class III heart failure and 7 age-matched healthy but sedentary controls. Patients and controls underwent blood sampling, echocardiography, measurement of peak VO2, daily activity assessment, and skeletal muscle biopsy.ResultsCompared to controls, skeletal muscle RyR1 in heart failure patients was excessively protein kinase A (PKA) phosphorylated (P*RyR1), S-nitrosylated (SNO) and oxidized (2, 4-dinitrophenyl hydrazine, DNP) and depleted of calstabin1. [figure 1]Figure: Quantification of immunoblots. Pooled data normalized to amount of immunoprecipitated RyR1. Arbitrary units, mean +/- standard deviation. This was associated with reduced peak VO2 and reduced daily activity.ConclusionsThis first in man study suggests that remodeling of skeletal muscle RyR1 occurs in heart failure and may contribute to skeletal muscle dysfunction, exercise intolerance, and reduced daily activity. Contraction of both cardiac and skeletal myocytes is dependent on cytoplasmic Ca2+. During muscle contraction, Ca2+ is released from the sarcoplasmic reticulum through a Ca2+ release channel, the ryanodine receptor, RyR. In heart failure, adrenergic stimulation leads to posttranslational modifications of cardiac muscle RyR (RyR2), resulting in pathological Ca2+ leak and impaired contractility. If similar remodeling of skeletal muscle RyR1 occurs in heart failure patients, and if this is associated with further impairment of physical capacity and activity is unknown. We studied 8 sedentary patients with New York Heart Association (NYHA) class III heart failure and 7 age-matched healthy but sedentary controls. Patients and controls underwent blood sampling, echocardiography, measurement of peak VO2, daily activity assessment, and skeletal muscle biopsy. Compared to controls, skeletal muscle RyR1 in heart failure patients was excessively protein kinase A (PKA) phosphorylated (P*RyR1), S-nitrosylated (SNO) and oxidized (2, 4-dinitrophenyl hydrazine, DNP) and depleted of calstabin1. [figure 1]Figure: Quantification of immunoblots. Pooled data normalized to amount of immunoprecipitated RyR1. Arbitrary units, mean +/- standard deviation. This was associated with reduced peak VO2 and reduced daily activity. This first in man study suggests that remodeling of skeletal muscle RyR1 occurs in heart failure and may contribute to skeletal muscle dysfunction, exercise intolerance, and reduced daily activity.