The phka1 deficient I/LnJ mouse exhibits endurance exercise deficiency with no compensatory changes in glycolytic gene expression


During exercise, phosphorylase kinase (PhK) is the key regulatory enzyme responsible for maintaining glycogenolytic flux to sustain muscle contraction. The absence of PhK in skeletal muscle results in glycogen storage disease (GSD) Type IX which is characterized by muscle weakness and rapid fatigue upon exercise. In this study, we have used the phka1 deficient I/LnJ mouse model of GSD to investigate the physiological and genetic adaptations that occur in response to voluntary exercise. When quantified over training periods of either 1, 2, or 5 weeks, I/LnJ mice ran significantly less time/day and distance/day than agematched C57/Bl6 mice. Cumulatively after five weeks, adult I/LnJ mice ran ~1/2 the total time and distance of wild-type mice, 116 ± 6 hours and 211 ±23 kmversus 194 ± 3 hours and 418 ±4 km, respectively. After 5 weeks, C57/Bl6 mice demonstrated an increase in endurance as a result of aerobic training; this observed physiological adaptation was not present in I/LnJ mice. The decrease in total distance run by I/LnJ mice was not due to a reduction in speed; juvenile and adult I/LnJ mice ran ~75% - 80% as fast as C57/Bl6 mice. When transcription of glycolytic genes glucose transporter 4 (scla1), pyruvate dehydrogenase (pdha1), and phosphofructokinase (pfk) were quantified at the end of each training period, no significant differences in expression levels were found between mouse strains, suggesting that non-glycolytic mechanisms work to maintain the muscle function observed in the I/LnJ mice.

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Mefford, A. , Ayers, C. , Rowland, N. and Rice, N. (2013) The phka1 deficient I/LnJ mouse exhibits endurance exercise deficiency with no compensatory changes in glycolytic gene expression. Open Journal of Molecular and Integrative Physiology, 3, 87-94. doi: 10.4236/ojmip.2013.32014.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Pickett-Gies, C.R. and Walsh, D.A. (1986) Phosphorylase kinase. In: Boyer, P.O. and Krebs, E.G., Eds., The Enzymes, Academic Press, Orlando, 395-459.
[2] Krebs, E.G. (1993) Nobel lecture. Protein phosphorylation and cellular regulation I. Bioscience Reports, 13, 127-142. doi:10.1007/BF01149958
[3] Brushia, R.J. and Walsh, D.A. (1999) Phosphorylase kinase: The complexity of its regulation is reflected in the complexity of its structure. Frontiers in Bioscience, 4, D618-D641. doi:10.2741/Brushia
[4] Heilmeyer Jr., L.M. (1991) Molecular basis of signal integration in phosphorylase kinase. Biochimica et Biophysica Acta, 1094, 168-174. doi:10.1016/0167-4889(91)90005-I
[5] Rice, N.A. and Carlson, G.M. (2001) Phosphorylase kinase. Wiley Encyclopedia of Molecular Medicine, John Wiley and Sons, Inc., New York, 2487-2490.
[6] Wehner, M., Clemens, P.R., Engel, A.G. and Kilimann, M.W. (1994) Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit. Human Molecular Genetics, 3, 1983-1987. doi:10.1093/hmg/3.11.1983
[7] Wuyts, W., Reyniers, E., Ceuterick, C., Storm, K., de Barsy, T. and Martin, J.J. (2005) Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene. American Journal of Medical Genetics Part A, 133, 82-84. doi:10.1002/ajmg.a.30517
[8] Burwinkel, B., Hu, B., Schroers, A., Clemens, P.R., Moses, S.W., Shin, Y.S., Pongratz, D., Vorgerd, M. and Kilimann, M.W. (2003) Muscle glycogenosis with low phosphorylase kinase activity: Mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. European Journal of Human Genetics, 11, 516-526. doi:10.1038/sj.ejhg.5200996
[9] Orngreen, M.C., Schelhaas, H.J., Jeppesen, T.D., Akman, H.O., Wevers, R.A., Andersen, S.T., Ter Laak, H.J., van Diggelen, O.P., DiMauro, S. and Vissing, J. (2008) Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology, 70, 1876-1882. doi:10.1212/01.wnl.0000289190.66955.67
[10] Abarbanel, J.M., Bashan, N., Potashnik, R., Osimani, A., Moses, S.W. and Herishanu, Y. (1986) Adult muscle phosphorylase “b” kinase deficiency. Neurology, 36, 560-562. doi:10.1212/WNL.36.4.560
[11] Cohen, P.T., Burchell, A. and Cohen, P. (1976) The molecular basis of skeletal muscle phosphorylase kinase deficiency. European Journal of Biochemistry, 66, 347-356. doi:10.1111/j.1432-1033.1976.tb10524.x
[12] Le Marchand-Brustel, Y., Cohen, P.T. and Cohen, P. (1979) Insulin activates glycogen synthase in phosphorylase kinase deficient mice. FEBS Letters, 105, 235-238. doi:10.1016/0014-5793(79)80619-5
[13] Bender, P.K. and Lalley, P.A. (1989) I/Lyn mouse phosphorylase kinase deficiency: Mutation disrupts expression of the alpha/alpha’-subunit mRNAs. Proceedings of the National Academy of Sciences of the USA, 86, 9996-10000. doi:10.1073/pnas.86.24.9996
[14] Bender, P.K. (1991) Phosphorylase kinase activity in I/strain neonatal skeletal muscle with a deficiency in alpha/alpha’ subunit mRNAs. Biochemical and Biophysical Research Communications, 179, 707-712. doi:10.1016/0006-291X(91)91430-K
[15] Schneider, A., Davidson, J.J., Wullrich, A. and Kilimann, M.W. (1993) Phosphorylase kinase deficiency in I-strain mice is associated with a frameshift mutation in the alpha subunit muscle isoform. Nature Genetics, 5, 381-385. doi:10.1038/ng1293-381
[16] Lyon Jr., J.B., Porter, J. and Robertson, M. (1967) Phosphorylase b kinase inheritance in mice. Science, 155, 1550-1551. doi:10.1126/science.155.3769.1550
[17] Gross, S.R. and Mayer, S.E. (1974) Characterization of the phosphorylase b to a converting activity in skeletal muscle extracts of mice with the phosphorylase b kinase deficiency mutation. The Journal of Biological Chemistry, 249, 6710-6718.
[18] Rahim, Z.H., Perrett, D., Lutaya, G. and Griffiths, J.R. (1980) Metabolic adaptation in phosphorylase kinase deficiency. Changes in metabolite concentrations during tetanic stimulation of mouse leg muscles. Biochemical Journal, 186, 331-341.
[19] Danforth, W.H. and Lyon Jr., J.B. (1964) Glycogenolysis during tetanic contraction of isolated mouse muscles in the presence and absence of phosphorylase A. The Journal of Biological Chemistry, 239, 4047-4050.
[20] Charron, M.J., Brosius 3rd, F.C., Alper, S.L. and Lodish, H.F. (1989) A glucose transport protein expressed predominately in insulin-responsive tissues. Proceedings of the National Academy of Sciences of the USA, 86, 2535-2539. doi:10.1073/pnas.86.8.2535
[21] James, D.E., Strube, M. and Mueckler, M. (1989) Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature, 338, 83-87. doi:10.1038/338083a0
[22] Fushiki, T., Wells, J.A., Tapscott, E.B. and Dohm, G.L. (1989) Changes in glucose transporters in muscle in response to exercise. American Journal of Physiology, 256, E580-E587.
[23] Ren, J.M., Semenkovich, C.F., Gulve, E.A., Gao, J. and Holloszy, J.O. (1994) Exercise induces rapid increases in GLUT4 expression, glucose transport capacity, and insulin-stimulated glycogen storage in muscle. The Journal of Biological Chemistry, 269, 14396-14401.
[24] Ploug, T., Stallknecht, B.M., Pedersen, O., Kahn, B.B., Ohkuwa, T., Vinten, J. and Galbo, H. (1990) Effect of endurance training on glucose transport capacity and glucose transporter expression in rat skeletal muscle. American Journal of Physiology, 259, E778-E786.
[25] Rodnick, K.J., Henriksen, E.J., James, D.E. and Holloszy, J.O. (1992) Exercise training, glucose transporters, and glucose transport in rat skeletal muscles. American Journal of Physiology, 262, C9-C14.
[26] Rovira, J., Irimia, J.M., Guerrero, M., Cadefau, J.A. and Cusso, R. (2012) Upregulation of heart PFK-2/FBPase-2 isozyme in skeletal muscle after persistent contraction. Pflügers Archiv—European Journal of Physiology, 463, 603-613. doi:10.1007/s00424-011-1068-5
[27] Zonderland, M.L., Bar, P.R., Reijneveld, J.C., Spruijt, B.M., Keizer, H.A. and Glatz, J.F. (1999) Different metabolic adaptation of heart and skeletal muscles to moderate-intensity treadmill training in the rat. European Journal of Applied Physiology and Occupational Physiology, 79, 391-396. doi:10.1007/s004210050527
[28] Allen, D.L., Harrison, B.C., Maass, A., Bell, M.L., Byrnes, W.C. and Leinwand, L.A. (2001) Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. Journal of Applied Physiology, 90, 1900-1908.
[29] McMullen, J.R. and Jennings, G.L. (2007) Differences between pathological and physiological cardiac hypertrophy: Novel therapeutic strategies to treat heart failure. Clinical and Experimental Pharmacology and Physiology, 34, 255-262. doi:10.1111/j.1440-1681.2007.04585.x
[30] Horckmans, M., Leon-Gomez, E., Robaye, B., Balligand, J.L., Boeynaems, J.M., Dessy, C. and Communi, D. (2012) Gene deletion of P2Y4 receptor lowers exercise capacity and reduces myocardial hypertrophy with swimming exercise. American Journal of Physiology—Heart and Circulatory Physiology, 303, H835-H843. doi:10.1152/ajpheart.00256.2012
[31] Sugden, M.C., Langdown, M.L., Harris, R.A. and Holness, M.J. (2000) Expression and regulation of pyruvate dehydrogenase kinase isoforms in the developing rat heart and in adulthood: Role of thyroid hormone status and lipid supply. Biochemical Journal, 352, 731-738. doi:10.1042/0264-6021:3520731
[32] Haller, R.G. (2008) Fueling around with glycogen: The implications of muscle phosphorylase b kinase deficiency. Neurology, 70, 1872-1873. doi:10.1212/01.wnl.0000312284.43608.46
[33] Echaniz-Laguna, A., Akman, H.O., Mohr, M., Tranchant, C., Talmant-Verbist, V., Rolland, M.O. and Dimauro, S. (2010) Muscle phosphorylase b kinase deficiency revisited. Neuromuscular Disorders, 20, 125-127. doi:10.1016/j.nmd.2009.11.004
[34] Chen, S.T., Chen, H.L., Ni, Y.H., Chien, Y.H., Jeng, Y.M., Chang, M.H. and Hwu, W.L. (2009) X-linked liver glycogenosis in a Taiwanese family: Transmission from undiagnosed males. Pediatrics & Neonatology, 50, 230-233. doi:10.1016/S1875-9572(09)60068-1
[35] Pears, J.S., Jung, R.T., Hopwood, D., Waddell, I.D. and Burchell, A. (1992) Glycogen storage disease diagnosed in adults. The Quarterly Journal of Medicine, 82, 207-222.
[36] Lyon Jr., J.B. and Porter, J. (1963) The relation of phosphorylase to glycogenolysis in skeletal muscle and heart of mice. The Journal of Biological Chemistry, 238, 1-11.
[37] Pederson, B.A., Cope, C.R., Schroeder, J.M., Smith, M.W., Irimia, J.M., Thurberg, B.L., De Paoli-Roach, A.A. and Roach, P.J. (2005) Exercise capacity of mice genetically lacking muscle glycogen synthase: In mice, muscle glycogen is not essential for exercise. The Journal of Biological Chemistry, 280, 17260-17265. doi:10.1074/jbc.M410448200

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