Impaired performance of skeletal muscle in alpha-glucosidase knockout mice

Glycogen storage disease type II (GSD II) is an inherited progressive muscle disease in which lack of functional acid alpha-glucosidase (AGLU) results in lysosomal accumulation of glycogen. We report on the impact of a null mutation of the acid alpha-glucosidase gene (AGLU(-/-)) in mice on the force production capabilities, contractile mass, oxidative capacity, energy status, morphology, and desmin content of skeletal muscle. Muscle function was assessed in halothane-anesthetized animals, using a recently designed murine isometric dynamometer. Maximal torque production during single tetanic contraction was 50% lower in the knockout mice than in wild type. Loss of developed torque was found to be disproportionate to the 20% loss in muscle mass. During a series of supramaximal contraction, fatigue, expressed as percentile decline of developed torque, did not differ between AGLU(-/-) mice and age-matched controls. Muscle oxidative capacity, energy status, and protein content (normalized to either dry or wet weight) were not changed in knockout mice compared to control. Alterations in muscle cell morphology were clearly visible. Desmin content was increased, whereas alpha-actinin was not. As the decline in muscle mass is insufficient to explain the degree in decline of mechanical performance, we hypothesize that the large clusters of noncontractile material present in the cytoplasm hamper longitudinal force transmission, and hence muscle contractile function. The increase in muscular desmin content is most likely reflecting adaptations to altered intracellular force transmission.