The sarcoplasmic reticulum in muscle fatigue and disease:: Role of the sarco(endo)plasmic reticulum Ca2+-ATPase

Skeletal muscles induced to contract repeatedly respond with a progressive loss in their ability to generate a target force or power This condition is known simply as fatigue. Commonly, fatigue may persist for prolonged periods of time, particularly at low activation frequencies, which is called low-frequency fatigue. Failure to activate the contractile apparatus with the appropriate intracellular free calcium ([Ca2+](f)) signal contributes to fatigue but the precise mechanisms involved are unknown. The sarcoplasmic reticulum (SR) is the major organelle in muscle that is responsible for the regulation of [Ca-f(2+]), and numerous studies have shown that SR function, both Ca2+ release and Ca2+ uptake, is impaired following fatiguing contractile activity. The major aim of this review is to provide insight into the various cellular mechanisms underlying the alterations in SR Ca2+ Cycling and cytosolic [Ca2+](f) that are associated both with the development of fatigue during repeated muscle contraction and with low-frequency or long-lasting fatigue. The primary focus will be on the role of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in normal muscle-function, fatigue, and disease.