β‐Adrenergic modulation of skeletal muscle contraction: key role of excitation–contraction coupling

摘要

Our aim is to describe the acute effects of catecholamines/β‐adrenergic agonists on contraction of non‐fatigued skeletal muscle in animals and humans, and explain the mechanisms involved. Adrenaline/β‐agonists (0.1–30 μm) generally augment peak force across animal species (positive inotropic effect) and abbreviate relaxation of slow‐twitch muscles (positive lusitropic effect). A peak force reduction also occurs in slow‐twitch muscles in some conditions. β2‐Adrenoceptor stimulation activates distinct cyclic AMP‐dependent protein kinases to phosphorylate multiple target proteins. β‐Agonists modulate sarcolemmal processes (increased resting membrane potential and action potential amplitude) via enhanced Na⁺–K⁺ pump and Na⁺–K⁺–2Cl⁻ cotransporter function, but this does not increase force. Myofibrillar Ca²⁺ sensitivity and maximum Ca²⁺‐activated force are unchanged. All force potentiation involves amplified myoplasmic Ca²⁺ transients consequent to increased Ca²⁺ release from sarcoplasmic reticulum (SR). This unequivocally requires phosphorylation of SR Ca²⁺ release channels/ryanodine receptors (RyR1) which sensitize the Ca²⁺‐induced Ca²⁺ release mechanism. Enhanced trans‐sarcolemmal Ca²⁺ influx through phosphorylated voltage‐activated Ca²⁺ channels contributes to force potentiation in diaphragm and amphibian muscle, but not mammalian limb muscle. Phosphorylation of phospholamban increases SR Ca²⁺ pump activity in slow‐twitch fibres but does not augment force; this process accelerates relaxation and may depress force. Greater Ca²⁺ loading of SR may assist force potentiation in fast‐twitch muscle. Some human studies show no significant force potentiation which appears to be related to the β‐agonist concentration used. Indeed high‐dose β‐agonists (∼0.1 μm) enhance SR Ca²⁺‐release rates, maximum voluntary contraction strength and peak Wingate power in trained humans. The combined findings can explain how adrenaline/β‐agonists influence muscle performance during exercise/stress in humans.