The timing and degree of contractile and metabolic activation of adult mammalian striated muscle is primarily regulated by cyclical release and sequestration of Ca2+ by the ryanodine-binding Ca2+- release channel and Ca2+-ATPase pump of the sarcoplasmic reticulum (SR). Of the two processes, Ca2+-uptake is much slower and rate-limiting. The SR activity is genetically limited according to species, individual, and fibre type, and is modulated in response to changing physiological demands by varying phosphorylation status for the short-term or by varying SR gene expression for the long-term. Ca2+-cycling activities correlate with twitch time in different skeletal muscle fibre types, and with heart rate in cardiac muscle from species differing in basal metabolic rate. Acute and chronic changes in heart rate produced by alterations in neural and endocrine stimulation, nutritional status, or in functional demand, are associated with equivalent changes in Ca2+-cycling activity. When performance demand exceeds capacity, energy imbalance and fatigue ensue in association with acute inhibition of the SR activity by accumulation of metabolic end-products. In cardiac muscle, if the imbalance persists, such as with cardiomyopathy, rate, volume, or pressure overload, or excessive endocrine stimulation, then SR Ca2+-cycling is down-regulated. This adaptive strategy minimises energy expenditure by the SR and contractile proteins and therefore resists development of fatigue, although at the expense of limiting performance capacity.
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