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Published on: September 18, 2017
Defects in ryanodine receptor calcium release in skeletal muscle from post-myocardial infarct rats
Abstract:
Defective calcium (Ca2+) signaling and impaired contractile function have been observed in skeletal muscle secondary to impaired myocardial function. However, the molecular basis for these muscle defects have not been identified. In this study, we evaluated the alterations of the ryanodine-sensitive Ca2+ release channels (RyR1) by analyzing global and local Ca2+ signaling in a rat postmyocardial infarction (PMI) model of myocardial overload. Ca2+ transients, measured with multiphoton imaging in individual fibers within a whole extensor digitorum longus (EDL) muscle, exhibited significantly reduced amplitude and a prolonged time course in PMI. Spatio-temporal properties of spontaneous Ca2+ sparks in fibers isolated from PMI EDL muscles were also significantly altered. In addition, RyR1 from PMI skeletal muscles were PKA-hyperphosphorylated and depleted of the FK506 binding protein (FKBP12). These data show that PMI skeletal muscles exhibit altered local Ca2+ signaling, associated with hyperphosphorylation of RyR1. The observed changes in Ca2+ signaling may contribute to defective excitation-contraction coupling in muscle that can contribute to the reduced exercise capacity in PMI, out of proportion to the degree of cardiac dysfunction.
Insights
Post-myocardial infarction (PMI) impairs skeletal muscle function by altering calcium (Ca2+) signaling. This study reveals ryanodine receptor 1 (RyR1) hyperphosphorylation and FKBP12 depletion in PMI skeletal muscles, contributing to exercise intolerance.
Area of Science:
- Physiology
- Molecular Biology
- Cardiovascular Research
Background:
- Skeletal muscle dysfunction and reduced exercise capacity are common in patients with heart disease.
- The molecular mechanisms linking cardiac dysfunction to skeletal muscle defects, particularly calcium (Ca2+) handling, remain unclear.
Purpose of the Study:
- To investigate alterations in skeletal muscle Ca2+ signaling and the ryanodine receptor 1 (RyR1) in a rat model of post-myocardial infarction (PMI).
- To identify molecular changes in RyR1 that may underlie impaired muscle function following cardiac injury.
Main Methods:
- Utilized a rat post-myocardial infarction (PMI) model to induce myocardial overload.
- Assessed global and local Ca2+ signaling in skeletal muscle fibers using multiphoton imaging.
- Analyzed Ca2+ transients, Ca2+ sparks, RyR1 phosphorylation, and FKBP12 levels in extensor digitorum longus (EDL) muscles.
Main Results:
- PMI skeletal muscle fibers exhibited significantly reduced Ca2+ transient amplitude and prolonged duration.
- Spontaneous Ca2+ sparks in isolated PMI EDL fibers showed altered spatio-temporal properties.
- Skeletal muscle RyR1 from PMI rats was hyperphosphorylated by PKA and depleted of FKBP12.
Conclusions:
- Post-myocardial infarction leads to significant alterations in skeletal muscle local Ca2+ signaling, specifically affecting RyR1 function.
- Hyperphosphorylation of RyR1 and FKBP12 depletion in skeletal muscle are key molecular changes associated with cardiac dysfunction.
- These Ca2+ signaling defects likely contribute to impaired excitation-contraction coupling and reduced exercise capacity in PMI, exceeding the expected level based on cardiac function alone.
