The Ca2 influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance

A Dayal, K Schrötter, Y Pan, K Föhr, W Melzer, M Grabner

Medical University of Innsbruck, Austria

Nature Communications

Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conventional function as Ca2+ channel is still enigmatic. Here we show that Ca2+ influx via DHPR is not necessary for muscle performance by generating a knock-in mouse where DHPR-mediated Ca2+ influx is eliminated. Homozygous knock-in mice display SR Ca2+ release, locomotor activity, motor coordination, muscle strength and susceptibility to fatigue comparable to wild-type controls, without any compensatory regulation of multiple key proteins of the EC coupling machinery and Ca2+ homeostasis. These findings support the hypothesis that the DHPR-mediated Ca2+ influx in mammalian skeletal muscle is an evolutionary remnant.

BIOSEB Instruments Used:
Spontaneous activity wheels (BIO-ACTIVW-M),Grip strength test (BIO-GS3),Treadmill (BX-TM),Passive avoidance (LE870)

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