The development of muscle fatigue due to exhaustive exercise is associated with impaired sarcoplasmic reticulum (SR) Ca-transport activity. This study tested the hypothesis that SR failure is a consistent feature of cardiac and skeletal muscle fatigue owing to relative functional overload regardless of the method of induction: excessive stimulation, diminished performance capacity, or excessive excitation-contraction coupling. The Ca-transport activity was determined using three unique models of muscle fatigue: chronic and rapid ventricular pacing in dogs; metabolic inhibition caused by global cardiac ischemia in swine; and the hypermetabolic syndrome of porcine malignant hyperthermia (MH). Both pacing- and ischemia-induced fatigue resulted in reduction of SR Ca-transport ATPase activity: from 275 +/- 58 to 159 +/- 57 nmol.min-1.mg-1 (mU/mg) and from 577 +/- 82 to 177 +/- 133 mU/mg, respectively. Both pacing-induced fatigue and halothane-induced MH resulted in reduction of Ca-sequestration activity of muscle homogenates from 5.95 +/- 2.4 to 3.11 +/- 0.67 nM/s at 300 nM Ca and 38.7 +/- 10.5 to 16.3 +/- 8.0 nM/s at 1500 nM Ca, respectively (all p less than 0.01). The isolated SR Ca-ATPase activity correlated with Ca-sequestration activity of myocardial homogenates (r = 0.76; p less than 0.005). Different models were used to study the relationship of Ca-transport activity with relaxation function, degree of acidosis, and ionized Ca concentration.(ABSTRACT TRUNCATED AT 250 WORDS)