Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ϳ90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

Work on the glucose-6-phosphatase system has intensified and diversified extensively in the past 3 years. The gene for the catalytic unit of the liver enzyme has been cloned from three species, and regulation at the level of gene expression is being studied in several laboratories worldwide. More than 20 sites of mutation in the catalytic unit protein have been demonstrated to underlie glycogenesis type 1a. inhibition of glucose-6-P hydrolysis by several newly identified competitive and time-dependent, irreversible inhibitors has been demonstrated and in several instances the predicted effects on liver glycogen formation and/or breakdown and on blood glucose production have been shown. Refinements in and additions to the presently dominant "substrate transport-catalytic unit" topological model for the glucose-6-phosphatase system have been made. A new model alternative to this, based on the "combined conformational flexibility-substrate transport" concept, has emerged. Experimental evidence for the phosphorylation of glucose in liver by high-K(m),glucose enzyme(s) in addition to glucokinase has continued to emerge, and new in vitro evidence supportive of biosynthetic functions of the glucose-6-phosphatase system in this role has appeared. High levels of multifunctional glucose-6-phosphatase have been shown present in pancreatic islet beta cells. Glucose-6-P has been established as the likely insulin secretagog in beta cells. Interesting differences in the temporal responses of glucose-6-phosphatase in kidney and liver have been demonstrated. An initial attempt is made here to meld the hepatic and pancreatic islet beta-cell glucose-6-phosphatase systems, and to a lesser extent the kidney tubular and small intestinal mucosal glucose-6-phosphatase systems into an integrated, coordinated mechanism involved in whole-body glucose homeostasis in health and disease.

The glucose storage polymer glycogen is generally considered to be an important source of energy for skeletal muscle contraction and a factor in exercise endurance. A genetically modified mouse model lacking muscle glycogen was used to examine whether the absence of the polysaccharide affects the ability of mice to run on a treadmill. The MGSKO mouse has the GYS1 gene, encoding the muscle isoform of glycogen synthase, disrupted so that skeletal muscle totally lacks glycogen. The morphology of the soleus and quadriceps muscles from MGSKO mice appeared normal. MGSKO-null mice, along with wild type littermates, were exercised to exhaustion. There were no significant differences in the work performed by MGSKO mice as compared with their wild type littermates. The amount of liver glycogen consumed during exercise was similar for MGSKO and wild type animals. Fasting reduced exercise endurance, and after overnight fasting, there was a trend to reduced exercise endurance for the MGSKO mice. These studies provide genetic evidence that in mice muscle glycogen is not essential for strenuous exercise and has relatively little effect on endurance.The two major repositories of glycogen, the polymeric storage form of glucose, are in the liver and skeletal muscle (1). In humans, these carbohydrate reserves are an important determinant of endurance upon sustained exercise, and muscle glycogen has long been viewed as a critical energy source during muscular activity (2-4). Depletion of muscle glycogen results in fatigue and impaired muscle performance and is a major determinant of endurance (2-5). Likewise, the ineffective utilization of muscle glycogen, as in patients with McArdle disease, leads to impaired exercise tolerance (6). In their "glycogen shunt" hypothesis, Shulman and Rothman (7) propose that glycogenolysis is the predominant source of energy for muscle contraction with glycogen acting essentially as an intermediate for blood glucose to enter glycolysis. Increasing muscle glycogen by manipulating diet and exercise regimens, a procedure termed "carbohydrate loading" or "glycogen supercompensation" (8), is adopted by endurance athletes to delay the onset of fatigue (4, 9 -11).Although the importance of adequate muscle glycogen to sustain exercise in humans has been well documented, caution is needed in extrapolating findings in rodents to humans. For instance, the amount of muscle glycogen, expressed as a fraction of body mass, is ϳ10-fold lower in mice than in humans (12, 13), whereas the corresponding values for liver glycogen are comparable (14). Thus, the relative role of these two glycogen storage depots may be different between the two species. The relative importance of muscle and liver glycogen stores as fuel sources for exercise has been studied extensively in rats (15-17). Exhaustive exercise either by treadmill running or swimming resulted in a reduction of muscle glycogen by 70 or Ͼ90%, respectively (15, 16). Both exercise methods reduced liver glycogen Ͼ90%. Using less strenuous exercise regimens, muscle g...

Glycogen is an important component of whole-body glucose metabolism. MGSKO mice lack skeletal muscle glycogen due to disruption of the GYS1 gene, which encodes muscle glycogen synthase. MGSKO mice were 5-10% smaller than wild-type littermates with less body fat. They have more oxidative muscle fibers and, based on the activation state of AMP-activated protein kinase, more capacity to oxidize fatty acids. Blood glucose in fed and fasted MGSKO mice was comparable to wild-type littermates. Serum insulin was lower in fed but not in fasted MGSKO animals. In a glucose tolerance test, MGSKO mice disposed of glucose more effectively than wild-type animals and had a more sustained elevation of serum insulin. This result was not explained by increased conversion to serum lactate or by enhanced storage of glucose in the liver. However, glucose infusion rate in a euglycemic-hyperinsulinemic clamp was normal in MGSKO mice despite diminished muscle glucose uptake. During the clamp, MGSKO animals accumulated significantly higher levels of liver glycogen as compared with wild-type littermates. Although disruption of the GYS1 gene negatively affects muscle glucose uptake, overall glucose tolerance is actually improved, possibly because of a role for GYS1 in tissues other than muscle. Diabetes 54: 3466 -3473, 2005 A fter a meal, glucose is distributed into various tissues of the body where it can be utilized as an energy source or stored as glycogen (1). Glycogen is a branched polymer of glucose residues connected by ␣-1,4-glycosidic linkages formed by the enzyme glycogen synthase (EC 2.4.1.11) and branchpoints formed via ␣-1,6-glycosidic linkages, introduced by the branching enzyme (EC 2.4.1.18). There are two mammalian isoforms of glycogen synthase. One, encoded by the GYS2 gene, appears to be expressed only in liver (2) while a second gene, GYS1, is expressed in skeletal and cardiac muscle as well as adipose tissue, kidney, and brain (3).Estimates of the contribution of skeletal muscle glycogen to glucose disposal after ingestion of carbohydrate vary. In humans, reports of ingested glucose conversion to muscle glycogen range from ϳ40% (4) up to 90% (5). It is widely accepted that muscle is an important site for glucose disposal and one might hypothesize that, in the absence of muscle glycogen, glucose clearance would be impaired. Consistent with this hypothesis, mutations in the GYS1 gene in humans have been implicated in certain diabetic populations with, for example, the Pro442Ala mutation resulting in decreased muscle glycogen synthase activity (6).We recently described the MGSKO mouse, in which the GYS1 gene is disrupted (7). Analysis of MGSKO mice confirmed the long-held supposition that glycogen synthase is required for glycogen synthesis since these animals were devoid of glycogen in cardiac and skeletal muscle (7). In the present study, we analyzed a number of metabolic parameters in the MGSKO mouse, including whole-body glucose metabolism, with an initial hypothesis that mice lacking the ability to synthesize muscl...

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