Exercise Capacity of Mice Genetically Lacking Muscle Glycogen Synthase

Abstract

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...

Role of 5′AMP-activated protein kinase in skeletal muscle

“…Thus, it has been speculated that liver glycogen rather than muscle glycogen is the preferred glucose source for mouse skeletal muscle during exercise. This view is supported by recent findings showing that manipulation of muscle glycogen content does not alter exercise performance in mice, 38,39 and that liver glycogen content is also depleted during exhaustive exercise. 40 If a2-AMPK KO mice are exercised at moderate intensity for 1 h, liver glycogen breakdown is markedly elevated compared with wild-type animals (unpublished observations).…”

Starch Binding Domain-containing Protein 1/Genethonin 1 Is a Novel Participant in Glycogen Metabolism

“…1C). Muscle glycogen can be acutely depleted to ϳ10% of the starting level by exercising mice to exhaustion on a treadmill (32). Such an exercise regimen did not affect muscle Stbd1 levels in wild type mice as judged by Western blotting (Fig.…”

“…Animals were maintained in AALAAC approved facilities of the Indiana University School of Medicine Laboratory Animal Research Center, with all experimental protocols approved by the Indiana University School of Medicine IACUC. The exercise protocol followed a previous study (32). Mice were sacrificed by cervical dislocation.…”

The Experimental Type 2 Diabetes Therapy Glycogen Phosphorylase Inhibition Can Impair Aerobic Muscle Function During Prolonged Contraction

“…It can also be argued that by utilizing a rodent model, we are underestimating the potential side effects of a nonselective GPi on endurance capacity, as data indicate that rodent or murine skeletal muscle relies less on endogenous muscle glycogen stores during prolonged exercise (37)(38)(39). Interestingly, in mice engineered to have greater muscle glycogen stores, endurance capacity is not enhanced and fatigue did not correspond with glycogen depletion (38).…”

“…As with all transgenic studies, evidence based on a single mutation with a single background strain can be challenging to interpret. In addition, when GYS1 (muscle glycogen synthase gene) is ablated (37), 90% of the animals die with cardiac abnormalities, while the survivors demonstrate an enhanced capacity for lipid oxidation (41), suggesting that genetic subgroup selection contributes to a net neutral endurance performance phenotype (37,41). Based on our data and the above discussion, it can be proposed that GPi compounds that show no tissue selectivity (1,3) may be detrimental to skeletal muscle energy metabolism and function during prolonged submaximal contraction.…”