Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis.
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.
García
Miguel
M
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Pujol
Anna
A
Ruzo
Albert
A
Riu
Efrén
E
Ruberte
Jesús
J
Arbós
Anna
A
Serafín
Anna
A
Albella
Beatriz
B
Felíu
Juan Emilio
JE
Bosch
Fátima
F
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
D006003:Glycogen; D010732:Phosphofructokinase-1; C068652:1-phosphofructokinase
J Biol Chem. 2002 Aug 23;277(34):30409-12
12087111
Blood. 1995 Dec 1;86(11):4323-30
7492793
Proc Natl Acad Sci U S A. 1980 Jan;77(1):62-6
6444721
J Biol Chem. 2007 Nov 9;282(45):32844-55
17716967
Curr Mol Med. 2002 Mar;2(2):197-212
11949936
Annu Rev Physiol. 2003;65:45-79
12524460
Clin Chest Med. 1994 Dec;15(4):661-74
7867281
J Neurol Sci. 1996 Sep 15;141(1-2):95-9
8880699
FASEB J. 1997 Jun;11(7):544-58
9212078
Arch Fr Pediatr. 1978 Dec;35(10):1105-15
155429
J Clin Invest. 1983 Dec;72(6):1995-2006
6227635
J Histochem Cytochem. 1957 Jul;5(4):420-36
13463314
Biochem J. 1987 Mar 15;242(3):667-71
2954542
Eur Respir J. 2005 Dec;26(6):1024-31
16319331
Proc Natl Acad Sci U S A. 1985 Dec;82(23):8109-13
2933748
J Biol Chem. 1979 Jul 10;254(13):5576-9
156182
Trends Genet. 2003 May;19(5):263-8
12711218
J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1108-15
16980655
Ann Hematol. 2005 Jun;84(6):353-7
15711802
Muscle Nerve. 1999 May;22(5):621-7
10331362
Adv Physiol Educ. 2006 Dec;30(4):145-51
17108241
J Child Neurol. 1989 Jul;4(3):186-8
2768781
Blood. 1985 Feb;65(2):345-51
3155631
J Clin Invest. 1999 Dec;104(12):1703-14
10606624
Acta Physiol Scand. 2000 Apr;168(4):657-65
10759602
Lancet. 1997 May 3;349(9061):1292
9142065
Isozymes Curr Top Biol Med Res. 1982;6:119-67
6219967
Curr Mol Med. 2002 Mar;2(2):189-96
11949935
Arch Neurol. 2002 Sep;59(9):1395-402
12223025
FASEB J. 2007 Nov;21(13):3431-41
17595346
Nature. 2008 Feb 21;451(7181):1008-12
18288196
Nat Genet. 1997 Jul;16(3):226-34
9207786
Neurology. 1986 Nov;36(11):1465-70
2945125
J Biol Chem. 2007 Dec 14;282(50):36642-51
17932032
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Hum Mutat. 1995;6(1):1-6
7550225
Blood. 2005 Apr 1;105(7):2741-8
15591122
J Am Vet Med Assoc. 1992 Nov 15;201(10):1569-71
1289336
N Engl J Med. 1991 Feb 7;324(6):364-9
1824792
South Med J. 2002 Dec;95(12):1436-40
12597313
J Intern Med. 2001 Jan;249(1):85-95
11168788
Ann Neurol. 1987 Jul;22(1):46-51
2957951
PLoS Biol. 2004 Oct;2(10):e294
15328533
Biochem Biophys Res Commun. 1965 May 3;19:517-23
14339001
Muscle Nerve. 1992 Apr;15(4):455-8
1533013
J Appl Physiol (1985). 1991 Mar;70(3):1201-7
1827789
Am J Physiol Endocrinol Metab. 2004 Mar;286(3):E347-53
14613927