Dihydropyridine Receptor Inhibition Attenuates Force and Fiber Cross-Sectional Area Decrease in the Three-Day Unloaded Rat Soleus Muscle

TL;DR

Blocking a specific calcium channel in rat muscles prevents muscle atrophy during unloading by reducing calcium release and preserving muscle function.

Contribution

This study shows that dihydropyridine receptor inhibition preserves muscle function during unloading by blocking calcium-dependent pathways.

Findings

Nifedipine treatment prevents decreases in muscle contractile properties during unloading.

DHPR inhibition reduces ATP, ROS, and Ca2+ accumulation in sarcoplasm and mitochondria.

Blocking DHPR preserves PGC1alpha mRNA and prevents cytoskeletal protein degradation.

Abstract

The depolarization of the sarcolemma is one of the first effects of unloading on skeletal muscle. We hypothesized that unloading-induced activation of the dihydropyridine receptor (DHPR), a voltage-sensitive L-type Ca2+ channel, and depolarization of the sarcolemma trigger intracellular Ca2+ release from the sarcoplasmic reticulum and activation of Ca2+-dependent signaling pathways, resulting in muscle atrophy. Nifedipine, a DHPR calcium channel blocker, was used to study the role of DHPR in the regulation of signaling pathways during three days of rat soleus muscle unloading/hindlimb suspension. Inhibition of the DHPR during unloading attenuates the decrease in soleus muscle contractile properties, prevents the accumulation of ATP, ROS, and Ca2+ content in the sarcoplasm and the mitochondria, and blocks the decrease in PGC1alpha mRNA expression and Junctophilin-1 (JP1) proteolysis. In nifedipine-treated rats, the improvement of the unloaded soleus muscle contractile properties could be mediated by blocking the calpain-mediated degradation of the cytoskeletal proteins. DHPR blocking could be one of the future directions for the preservation of contractile properties of inactive/unloaded muscle.

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