title: Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis.
abstract: Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exercise intolerance. PFKM deficiency is considered as a skeletal muscle glycogenosis, but the relative contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. To elucidate this issue, we have generated mice deficient for PFKM (Pfkm(-/-)). Here, we show that Pfkm(-/-) mice had high lethality around weaning and reduced lifespan, because of the metabolic alterations. In skeletal muscle, including respiratory muscles, the lack of PFK activity blocked glycolysis and resulted in considerable glycogen storage and low ATP content. Although erythrocytes of Pfkm(-/-) mice preserved 50% of PFK activity, they showed strong reduction of 2,3-biphosphoglycerate concentrations and hemolysis, which was associated with compensatory reticulocytosis and splenomegaly. As a consequence of these haematological alterations, and of reduced PFK activity in the heart, Pfkm(-/-) mice developed cardiac hypertrophy with age. Taken together, these alterations resulted in muscle hypoxia and hypervascularization, impaired oxidative metabolism, fiber necrosis, and exercise intolerance. These results indicate that, in GSDVII, marked alterations in muscle bioenergetics and erythrocyte metabolism interact to produce a complex systemic disorder. Therefore, GSDVII is not simply a muscle glycogenosis, and Pfkm(-/-) mice constitute a unique model of GSDVII which may be useful for the design and assessment of new therapies.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: García
authors.forename: Anna
authors.initials: A
authors.lastname: Pujol
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.forename: Efrén
authors.initials: E
authors.lastname: Riu
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.forename: Anna
authors.initials: A
authors.lastname: Arbós
authors.forename: Anna
authors.initials: A
authors.lastname: Serafín
authors.forename: Beatriz
authors.initials: B
authors.lastname: Albella
authors.forename: Juan Emilio
authors.initials: JE
authors.lastname: Felíu
authors.forename: Fátima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006014:Glycogen Storage Disease Type VII / Q000150:complications / Q000201:enzymology* / Q000378:metabolism; D006402:Hematologic Diseases / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010732:Phosphofructokinase-1 / Q000172:deficiency* / Q000235:genetics
chemical_list: D006003:Glycogen; D010732:Phosphofructokinase-1; C068652:1-phosphofructokinase
references.citation: J Biol Chem. 2002 Aug 23;277(34):30409-12
references.pmid: 12087111
references.citation: Blood. 1995 Dec 1;86(11):4323-30
references.pmid: 7492793
references.citation: Proc Natl Acad Sci U S A. 1980 Jan;77(1):62-6
references.pmid: 6444721
references.citation: J Biol Chem. 2007 Nov 9;282(45):32844-55
references.pmid: 17716967
references.citation: Curr Mol Med. 2002 Mar;2(2):197-212
references.pmid: 11949936
references.citation: Annu Rev Physiol. 2003;65:45-79
references.pmid: 12524460
references.citation: Clin Chest Med. 1994 Dec;15(4):661-74
references.pmid: 7867281
references.citation: J Neurol Sci. 1996 Sep 15;141(1-2):95-9
references.pmid: 8880699
references.citation: FASEB J. 1997 Jun;11(7):544-58
references.pmid: 9212078
references.citation: Arch Fr Pediatr. 1978 Dec;35(10):1105-15
references.pmid: 155429
references.citation: J Clin Invest. 1983 Dec;72(6):1995-2006
references.pmid: 6227635
references.citation: J Histochem Cytochem. 1957 Jul;5(4):420-36
references.pmid: 13463314
references.citation: Biochem J. 1987 Mar 15;242(3):667-71
references.pmid: 2954542
references.citation: Eur Respir J. 2005 Dec;26(6):1024-31
references.pmid: 16319331
references.citation: Proc Natl Acad Sci U S A. 1985 Dec;82(23):8109-13
references.pmid: 2933748
references.citation: J Biol Chem. 1979 Jul 10;254(13):5576-9
references.pmid: 156182
references.citation: Trends Genet. 2003 May;19(5):263-8
references.pmid: 12711218
references.citation: J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1108-15
references.pmid: 16980655
references.citation: Ann Hematol. 2005 Jun;84(6):353-7
references.pmid: 15711802
references.citation: Muscle Nerve. 1999 May;22(5):621-7
references.pmid: 10331362
references.citation: Adv Physiol Educ. 2006 Dec;30(4):145-51
references.pmid: 17108241
references.citation: J Child Neurol. 1989 Jul;4(3):186-8
references.pmid: 2768781
references.citation: Blood. 1985 Feb;65(2):345-51
references.pmid: 3155631
references.citation: J Clin Invest. 1999 Dec;104(12):1703-14
references.pmid: 10606624
references.citation: Acta Physiol Scand. 2000 Apr;168(4):657-65
references.pmid: 10759602
references.citation: Lancet. 1997 May 3;349(9061):1292
references.pmid: 9142065
references.citation: Isozymes Curr Top Biol Med Res. 1982;6:119-67
references.pmid: 6219967
references.citation: Curr Mol Med. 2002 Mar;2(2):189-96
references.pmid: 11949935
references.citation: Arch Neurol. 2002 Sep;59(9):1395-402
references.pmid: 12223025
references.citation: FASEB J. 2007 Nov;21(13):3431-41
references.pmid: 17595346
references.citation: Nature. 2008 Feb 21;451(7181):1008-12
references.pmid: 18288196
references.citation: Nat Genet. 1997 Jul;16(3):226-34
references.pmid: 9207786
references.citation: Neurology. 1986 Nov;36(11):1465-70
references.pmid: 2945125
references.citation: J Biol Chem. 2007 Dec 14;282(50):36642-51
references.pmid: 17932032
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Hum Mutat. 1995;6(1):1-6
references.pmid: 7550225
references.citation: Blood. 2005 Apr 1;105(7):2741-8
references.pmid: 15591122
references.citation: J Am Vet Med Assoc. 1992 Nov 15;201(10):1569-71
references.pmid: 1289336
references.citation: N Engl J Med. 1991 Feb 7;324(6):364-9
references.pmid: 1824792
references.citation: South Med J. 2002 Dec;95(12):1436-40
references.pmid: 12597313
references.citation: J Intern Med. 2001 Jan;249(1):85-95
references.pmid: 11168788
references.citation: Ann Neurol. 1987 Jul;22(1):46-51
references.pmid: 2957951
references.citation: PLoS Biol. 2004 Oct;2(10):e294
references.pmid: 15328533
references.citation: Biochem Biophys Res Commun. 1965 May 3;19:517-23
references.pmid: 14339001
references.citation: Muscle Nerve. 1992 Apr;15(4):455-8
references.pmid: 1533013
references.citation: J Appl Physiol (1985). 1991 Mar;70(3):1201-7
references.pmid: 1827789
references.citation: Am J Physiol Endocrinol Metab. 2004 Mar;286(3):E347-53
references.pmid: 14613927