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 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 (1Roach P.J. Skurat A.V. Harris R.A. Cherrington A.D. Jefferson L.S. The Endocrine Pancreas and Regulation of Metabolism. Oxford University Press, New York2001Google Scholar). 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 (2Bergstrom J. Hermansen L. Hultman E. Saltin B. Acta Physiol. Scand. 1967; 71: 140-150Crossref PubMed Scopus (1193) Google Scholar, 3Holloszy J.O. Kohrt W.M. Hansen P.A. Front. Biosci. 1998; 3: D1011-D1027Crossref PubMed Google Scholar, 4Ivy J.L. Clin. Sports Med. 1999; 18: 469-484Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Depletion of muscle glycogen results in fatigue and impaired muscle performance and is a major determinant of endurance (2Bergstrom J. Hermansen L. Hultman E. Saltin B. Acta Physiol. Scand. 1967; 71: 140-150Crossref PubMed Scopus (1193) Google Scholar, 3Holloszy J.O. Kohrt W.M. Hansen P.A. Front. Biosci. 1998; 3: D1011-D1027Crossref PubMed Google Scholar, 4Ivy J.L. Clin. Sports Med. 1999; 18: 469-484Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 5Karlsson J. Saltin B. J. Appl. Physiol. 1971; 31: 203-206Crossref PubMed Scopus (287) Google Scholar). Likewise, the ineffective utilization of muscle glycogen, as in patients with McArdle disease, leads to impaired exercise tolerance (6McArdle B. Clin. Sci. (Lond.). 1951; 10: 13-33PubMed Google Scholar). In their “glycogen shunt” hypothesis, Shulman and Rothman (7Shulman R.G. Rothman D.L. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 457-461Crossref PubMed Scopus (112) Google Scholar) 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” (8Bergstrom J. Hultman E. Nature. 1966; 210: 309-310Crossref PubMed Scopus (336) Google Scholar), is adopted by endurance athletes to delay the onset of fatigue (4Ivy J.L. Clin. Sports Med. 1999; 18: 469-484Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 9Sherman W.M. Costill D.L. Fink W.J. Miller J.M. Int. J. Sports Med. 1981; 2: 114-118Crossref PubMed Scopus (246) Google Scholar, 10Hermansen L. Hultman E. Saltin B. Acta Physiol. Scand. 1967; 71: 129-139Crossref PubMed Scopus (495) Google Scholar, 11Hawley J.A. Schabort E.J. Noakes T.D. Dennis S.C. Sports Med. 1997; 24: 73-81Crossref PubMed Scopus (176) Google Scholar). 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 ∼10-fold lower in mice than in humans (12Kasuga M. Ogawa W. Ohara T. J. Clin. Investig. 2003; 111: 1282-1284Crossref PubMed Google Scholar, 13Hribal M.L. Oriente F. Accili D. Am. J. Physiol. 2002; 282: E977-E981Crossref PubMed Scopus (51) Google Scholar), whereas the corresponding values for liver glycogen are comparable (14Orho M. Bosshard N.U. Buist N.R. Gitzelmann R. Aynsley-Green A. Blumel P. Gannon M.C. Nuttall F.Q. Groop L.C. J. Clin. Investig. 1998; 102: 507-515Crossref PubMed Scopus (99) Google Scholar). 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 (15Reitman J. Baldwin K.M. Holloszy J.O. Proc. Soc. Exp. Biol. Med. 1973; 142: 628-631Crossref PubMed Scopus (61) Google Scholar, 16Terjung R.L. Baldwin K.M. Mole P.A. Klinkerfuss G.H. Holloszy J.O. Am. J. Physiol. 1972; 223: 549-554Crossref PubMed Scopus (43) Google Scholar, 17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). Exhaustive exercise either by treadmill running or swimming resulted in a reduction of muscle glycogen by 70 or >90%, respectively (15Reitman J. Baldwin K.M. Holloszy J.O. Proc. Soc. Exp. Biol. Med. 1973; 142: 628-631Crossref PubMed Scopus (61) Google Scholar, 16Terjung R.L. Baldwin K.M. Mole P.A. Klinkerfuss G.H. Holloszy J.O. Am. J. Physiol. 1972; 223: 549-554Crossref PubMed Scopus (43) Google Scholar). Both exercise methods reduced liver glycogen >90%. Using less strenuous exercise regimens, muscle glycogen stores were depleted 40–70%, depending on muscle type, whereas liver glycogen stores were reduced ∼85% (17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). Although significant amounts of muscle glycogen were consumed, the authors suggest that, in contrast to humans, rats may be more dependent on liver glycogen stores for exercise (17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). Several genetically modified mouse lines with altered muscle metabolism have been analyzed for exercise endurance. Mice lacking the type 1 protein phosphatase glycogen-targeting subunit, RGL (GM) (18Suzuki Y. Lanner C. Kim J.H. Vilardo P.G. Zhang H. Yang J. Cooper L.D. Steele M. Kennedy A. Bock C.B. Scrimgeour A. Lawrence Jr., J.C. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar) have ∼10% of wild type muscle glycogen levels and exhibit a 60% decrease in work capacity (19Aschenbach W.G. Suzuki Y. Breeden K. Prats C. Hirshman M.F. Dufresne S.D. Sakamoto K. Vilardo P.G. Steele M. Kim J.H. Jing S.L. Goodyear L.J. DePaoli-Roach A.A. J. Biol. Chem. 2001; 276: 39959-39967Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Overexpression of RGL resulted in a 3–4-fold increase in skeletal muscle glycogen but had no effect on exercise tolerance (19Aschenbach W.G. Suzuki Y. Breeden K. Prats C. Hirshman M.F. Dufresne S.D. Sakamoto K. Vilardo P.G. Steele M. Kim J.H. Jing S.L. Goodyear L.J. DePaoli-Roach A.A. J. Biol. Chem. 2001; 276: 39959-39967Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Mice with muscle-specific disruption of the gene encoding the GLUT4 glucose transporter have normal muscle glycogen levels but are impaired in their ability to exercise (20Wallberg-Henriksson H. Zierath J.R. Mol. Membr. Biol. 2001; 18: 205-211Crossref PubMed Scopus (78) Google Scholar). Recently, mouse models have been described in which genetic manipulation affected the oxidative capacity of muscles and physical endurance (21Mason S.D. Howlett R.A. Kim M.J. Olfert I.M. Hogan M.C. McNulty W. Hickey R.P. Wagner P.D. Kahn C.R. Giordano F.J. Johnson R.S. PLoS Biol. 2004; 2: E288Crossref PubMed Scopus (159) Google Scholar, 22Wang Y.X. Zhang C.L. Yu R.T. Cho H.K. Nelson M.C. Bayuga-Ocampo C.R. Ham J. Kang H. Evans R.M. PLoS Biol. 2004; 2: E294Crossref PubMed Scopus (878) Google Scholar). Overexpression of PPARδ 1The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; WT, wild type; IL-6, interleukin-6. 1The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; WT, wild type; IL-6, interleukin-6. caused a significant switch to more oxidative muscle fibers and increased exercise endurance (22Wang Y.X. Zhang C.L. Yu R.T. Cho H.K. Nelson M.C. Bayuga-Ocampo C.R. Ham J. Kang H. Evans R.M. PLoS Biol. 2004; 2: E294Crossref PubMed Scopus (878) Google Scholar). Conversely, disruption of the PPARδ gene led to a significant reduction in run time (22Wang Y.X. Zhang C.L. Yu R.T. Cho H.K. Nelson M.C. Bayuga-Ocampo C.R. Ham J. Kang H. Evans R.M. PLoS Biol. 2004; 2: E294Crossref PubMed Scopus (878) Google Scholar). In a different model, mice lacking PPARα deplete liver but not muscle glycogen more rapidly than wild type littermates when subjected to exhaustive exercise (23Muoio D.M. MacLean P.S. Lang D.B. Li S. Houmard J.A. Way J.M. Winegar D.A. Corton J.C. Dohm G.L. Kraus W.E. J. Biol. Chem. 2002; 277: 26089-26097Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). This liver glycogen depletion correlates with reduced exercise performance in the null animals (23Muoio D.M. MacLean P.S. Lang D.B. Li S. Houmard J.A. Way J.M. Winegar D.A. Corton J.C. Dohm G.L. Kraus W.E. J. Biol. Chem. 2002; 277: 26089-26097Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). Loss of muscle HIF-1α suppressed exercise-induced expression of a number of genes and caused a change to more oxidative muscle metabolism in the null animals (21Mason S.D. Howlett R.A. Kim M.J. Olfert I.M. Hogan M.C. McNulty W. Hickey R.P. Wagner P.D. Kahn C.R. Giordano F.J. Johnson R.S. PLoS Biol. 2004; 2: E288Crossref PubMed Scopus (159) Google Scholar). This metabolic modification correlated with increased exercise capacity, but repeated bouts of activity ultimately led to increased muscle damage compared with controls. Bulk synthesis and degradation of glycogen are catalyzed by glycogen synthase and glycogen phosphorylase, respectively, in concert with branching and debranching enzymes. The enzymology of glycogen metabolism is tissue-specific. For example, glycogen synthase (EC 2.4.1.11), the enzyme responsible for forming the basic α-1,4 polymeric linkages of glycogen, is encoded by the GYS2 gene in liver and the GYS1 gene in skeletal muscle and most other tissues. We recently obtained from Lexicon Genetics Incorporated a genetically modified mouse (MGSKO) in which the GYS1 gene is disrupted (24Pederson B.A. Chen H. Schroeder J.M. Shou W. DePaoli-Roach A.A. Roach P.J. Mol. Cell. Biol. 2004; 24: 7179-7187Crossref PubMed Scopus (89) Google Scholar). The homozygous null animals are devoid of glycogen in skeletal muscle, heart, and several other tissues (24Pederson B.A. Chen H. Schroeder J.M. Shou W. DePaoli-Roach A.A. Roach P.J. Mol. Cell. Biol. 2004; 24: 7179-7187Crossref PubMed Scopus (89) Google Scholar). The MGSKO mouse model provides an interesting genetic model with which to assess the role of muscle glycogen in exercise endurance. We hypothesized that MGSKO mice might be impaired in their ability to perform exhaustive exercise. In addition, the inability to synthesize glycogen in the muscle allows us to test the notion that glucose is first converted to glycogen and subsequently degraded before entering glycolysis (7Shulman R.G. Rothman D.L. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 457-461Crossref PubMed Scopus (112) Google Scholar). Mouse Background and Husbandry—MGSKO heterozygous mice were generated from the Lexicon Genetics Omnibank library of gene-trapped ES cells (24Pederson B.A. Chen H. Schroeder J.M. Shou W. DePaoli-Roach A.A. Roach P.J. Mol. Cell. Biol. 2004; 24: 7179-7187Crossref PubMed Scopus (89) Google Scholar). Breeders, generated by mating these heterozygotes with C57BL/6J were to the null animals in mice were in and with a and were and were in the for of of were by the University and exercise mice were for on a treadmill the first the treadmill was to and the was and was increased by 1 during the For the was increased by The was increased to and on For the mice were run on a treadmill a with an of The was increased by 1 and after the of the exercise. For mice for was and mice were exercised For overnight fasting, was and mice were run the A was to mice that of the treadmill Mice were run to as by of mice to on the treadmill performed body running running time of mice was in the and in with the of in for the and of the glucose and were before and after exercise from blood with a and of for were by skeletal muscle and liver were rapidly in and in was in of by glucose from glycogen by the of E. F. H. of Press, New Scholar) as described by Suzuki (18Suzuki Y. Lanner C. Kim J.H. Vilardo P.G. Zhang H. Yang J. Cooper L.D. Steele M. Kennedy A. Bock C.B. Scrimgeour A. Lawrence Jr., J.C. DePaoli-Roach A.A. Mol. Cell. Biol. 2001; 21: 2683-2694Crossref PubMed Scopus (129) Google Scholar). are as values was with the and quadriceps muscles were from MGSKO and wild type littermates. were rapidly and in in by in in The tissues were overnight and in were with procedure and with This results in in which of glycogen are well and a of were with a and with the 1 for the were from these for were and were was with for by for The were in a were and on MGSKO MGSKO mouse has the GYS1 gene disrupted and lacks glycogen synthase and glycogen in several tissues skeletal muscle, heart, and The of glycogen to a and ∼10% of the null mice (24Pederson B.A. Chen H. Schroeder J.M. Shou W. DePaoli-Roach A.A. Roach P.J. Mol. Cell. Biol. 2004; 24: 7179-7187Crossref PubMed Scopus (89) Google Scholar). mice, are normal with that are as by and that are not (24Pederson B.A. Chen H. Schroeder J.M. Shou W. DePaoli-Roach A.A. Roach P.J. Mol. Cell. Biol. 2004; 24: 7179-7187Crossref PubMed Scopus (89) Google Scholar). We skeletal muscle by to whether the absence of glycogen had of soleus and muscle from the MGSKO mice by not as compared with wild type littermates The was the of for the quadriceps and of MGSKO of MGSKO there was no in compared with wild type littermates. test whether there were more differences in mice were for an in with in the and was by the with which the were a of there was no significant in activity between MGSKO and wild type mice. MGSKO mice to be more during the and less during the but the differences were of the importance of glycogen for sustained strenuous exercise, and mice were subjected to treadmill running the described the treadmill was increased and There was no significant in the running time for for or the work performed by mice MGSKO mice than wild type littermates for for Both and MGSKO mice have lower body reduction for and reduction for as compared with wild type littermates. A. M. W. and P. J. in body is in the of work the between was not significant differences in running to on the mouse studied M.J. M. A. 2004; PubMed Scopus Google Scholar). blood glucose was not different between MGSKO and wild type mice a and and exercise caused a similar decrease in a and during exercise glycolysis and be a factor for exercise blood levels were lower in the MGSKO mice and and were increased by exercise. the increase was in the MGSKO animals and The exercise muscle glycogen in wild type mice from to of work in rats R.L. Baldwin K.M. Mole P.A. Klinkerfuss G.H. Holloszy J.O. Am. J. Physiol. 1972; 223: 549-554Crossref PubMed Scopus (43) Google Scholar, 17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar) has that to levels of muscle glycogen, glycogen be depleted from and depletion in muscle when the the capacity of and intermediate fibers R.L. Baldwin K.M. Mole P.A. Klinkerfuss G.H. Holloszy J.O. Am. J. Physiol. 1972; 223: 549-554Crossref PubMed Scopus (43) Google Scholar, 17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). that treadmill subjected the mice to a relatively exercise In these liver glycogen not for the absence of muscle glycogen in the MGSKO mice by the amount in exercise of wild type and MGSKO glucose MGSKO MGSKO MGSKO MGSKO MGSKO exercise. in a exercise of overnight wild type and MGSKO glucose MGSKO MGSKO MGSKO MGSKO MGSKO MGSKO MGSKO MGSKO exercise. in a of exercise on blood glucose and in wild type and MGSKO mice. and after exercise, glucose and and and were in blood from and and and wild type and MGSKO animals. compared with the before exercise. compared with wild type in the exercise of exercise on liver glycogen in wild type and MGSKO mice. from wild type and MGSKO mice before and after exercise were analyzed for glycogen as described compared with before and liver glycogen is consumed during the exercise levels were reduced by to treadmill exercise to test whether muscle glycogen a importance as a determinant of run deplete liver glycogen, mice were for to a decrease or overnight to a decrease in glycogen levels in In contrast to muscle glycogen stores of the wild type mice are not affected by a overnight of a the work performed by wild type and MGSKO animals was compared with animals for and MGSKO mice overnight reduced liver glycogen to ∼10% of the levels in mice MGSKO of of MGSKO and correlated with a significant reduction in the exercise capacity of the animals type mice performed of the work in the whereas MGSKO mice were of of their work performance blood glucose levels were lower in mice compared with mice, but there were no differences between and reduced levels in that there was no between wild type and MGSKO animals levels the of exercise were reduced with and of to a in wild type than MGSKO mice and Although the is that muscle glycogen is an important determinant for exercise capacity in humans J.O. Kohrt W.M. Hansen P.A. Front. Biosci. 1998; 3: D1011-D1027Crossref PubMed Google Scholar, 4Ivy J.L. Clin. Sports Med. 1999; 18: 469-484Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar), may not be for with rats suggest that liver glycogen may be more important than muscle glycogen for exercise (15Reitman J. Baldwin K.M. Holloszy J.O. Proc. Soc. Exp. Biol. Med. 1973; 142: 628-631Crossref PubMed Scopus (61) Google Scholar, 16Terjung R.L. Baldwin K.M. Mole P.A. Klinkerfuss G.H. Holloszy J.O. Am. J. Physiol. 1972; 223: 549-554Crossref PubMed Scopus (43) Google Scholar, 17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). with several mouse models with genetically muscle glucose metabolism has not a on the of muscle glycogen as in the in rats and mice, muscle glycogen is during exercise and as a source of fuel for The MGSKO mice, which have no skeletal muscle glycogen, a genetic model with which to test the importance of muscle glycogen. In these animals normal physical activity and were not impaired in their performance of exhaustive exercise. after overnight to deplete the liver glycogen a trend to endurance in the MGSKO animals is that of muscle glycogen might have a on performance other exercise as muscular as in the of for humans. an with mice is of MGSKO after the that the of animals studied is to exercise of the of factor that for their in the first have evidence for as the that normal exercise performance is in the absence of muscle glycogen. be of to in of muscle The other that between wild type and MGSKO mice was blood before and after exercise. The reduced blood in MGSKO mice is to reduced glycolysis in the absence of muscle glycogen increased of to be used as a by the by muscle glycogen have been by the of liver glycogen in MGSKO on of major energy in the there is the that impaired muscle glycogen metabolism affects liver has been that exercise muscle to increase of IL-6, which in to the liver to increase glycogen A. C. C. P. P. M. Saltin B. J. Cell. 2003; 24: PubMed Scopus Google Scholar, M. 2004; PubMed Scopus Google Scholar). by the muscle is increased as glycogen is depleted M. Biol. PubMed Google Scholar, A. T. P. Saltin B. J. Physiol. (Lond.). 2001; Scopus Google Scholar). We levels in MGSKO mice and no significant of the of muscle glycogen on either or exercise-induced A. M. W. C. R. J. M. and P. J. In liver glycogen during exercise was the in wild type and MGSKO mice, that the in energy to the of muscle glycogen from an are increased of glucose with blood from liver glycogen or the of and increased of and in skeletal muscle from MGSKO animals is with E. B. A. and P. J. mouse model with increased oxidative capacity, has increased exercise performance compared with wild type littermates. This that a switch to more oxidative metabolism has the to the of muscle glycogen as a fuel in MGSKO mice. The that MGSKO animals are glucose by liver glycogen to fuel exercise the of glucose converted to glycogen in muscle to entering glycolysis as by Shulman and Rothman (7Shulman R.G. Rothman D.L. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 457-461Crossref PubMed Scopus (112) Google Scholar). the that T. H. Y. J.L. D.A. S.C. R. Med. 2002; PubMed Scopus Google Scholar) of the body of a mouse is muscle and the of the the amount of glycogen used during the exhaustive exercise type mice used of glucose 70 from muscle and from liver glycogen, whereas MGSKO mice of glucose from In a normal mouse glucose of glycogen are and in muscle and in mice there is more glycogen in the liver of a than in skeletal A similar of liver to muscle glycogen has been in rats (17Baldwin K.M. Reitman J.S. Terjung R.L. Winder W.W. Holloszy J.O. Am. J. Physiol. 1973; 225: 1045-1050Crossref PubMed Scopus (110) Google Scholar). In humans more glycogen in skeletal muscle than in liver (4Ivy J.L. Clin. Sports Med. 1999; 18: 469-484Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). There a in the of glycogen in mice and rats humans, a that may the manipulation of muscle glycogen had little on the ability of mice to exercise, whereas in humans the importance of glycogen is well for example, by McArdle The reduction of liver glycogen with time of correlated with a ability to perform This effect was in MGSKO mice, and after a there was a trend for null mice to perform less work than wild type littermates. Thus, than muscle, glycogen the onset of exercise may be a determinant of the exercise capacity of mice. (23Muoio D.M. MacLean P.S. Lang D.B. Li S. Houmard J.A. Way J.M. Winegar D.A. Corton J.C. Dohm G.L. Kraus W.E. J. Biol. Chem. 2002; 277: 26089-26097Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar) that when mice were run to on a treadmill exercise fatigue correlated with liver than muscle glycogen with the of liver glycogen depletion in mice was increased as compared with wild type littermates and correlated with fatigue upon exhaustive treadmill exercise (23Muoio D.M. MacLean P.S. Lang D.B. Li S. Houmard J.A. Way J.M. Winegar D.A. Corton J.C. Dohm G.L. Kraus W.E. J. Biol. Chem. 2002; 277: 26089-26097Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar). This is with the by Reitman (15Reitman J. Baldwin K.M. Holloszy J.O. Proc. Soc. Exp. Biol. Med. 1973; 142: 628-631Crossref PubMed Scopus (61) Google Scholar) that liver glycogen may be more important than muscle glycogen for exercise in In the MGSKO mouse provides genetic evidence that there is no of glycogen for muscular activity in mice. in mice the synthesis of muscle glycogen is not a for glucose to enter glycolysis. liver glycogen is may of muscle glycogen for exercise activity was the University of Mouse in by of We J. L. R. A. J. C. and for for with the