title: Low bone strength is a manifestation of phenylketonuria in mice and is attenuated by a glycomacropeptide diet.
abstract: OBJECTIVE
  Phenylketonuria (PKU), caused by phenylalanine (phe) hydroxylase loss of function mutations, requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP), a low-phe whey protein, provides a palatable alternative to AA formula. Skeletal fragility is a poorly understood chronic complication of PKU. We sought to characterize the impact of the PKU genotype and dietary protein source on bone biomechanics.
  
  
  METHODS
  Wild type (WT; Pah(+/+)) and PKU (Pah(enu2/enu2)) mice on a C57BL/6J background were fed high-phe casein, low-phe AA, and low-phe GMP diets between 3 to 23 weeks of age. Following euthanasia, femur biomechanics were assessed by 3-point bending and femoral diaphyseal structure was determined. Femoral ex vivo bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Whole bone parameters were used in principal component analysis. Data were analyzed by 3-way ANCOVA with genotype, sex, and diet as the main factors.
  
  
  RESULTS
  Regardless of diet and sex, PKU femora were more brittle, as manifested by lower post-yield displacement, weaker, as manifested by lower energy and yield and maximal loads, and showed reduced BMD compared with WT femora. Four principal components accounted for 87% of the variance and all differed significantly by genotype. Regardless of genotype and sex, the AA diet reduced femoral cross-sectional area and consequent maximal load compared with the GMP diet.
  
  
  CONCLUSIONS
  Skeletal fragility, as reflected in brittle and weak femora, is an inherent feature of PKU. This PKU bone phenotype is attenuated by a GMP diet compared with an AA diet.
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Solverson
authors.forename: Sangita G
authors.initials: SG
authors.lastname: Murali
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Litscher
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blank
authors.forename: Denise M
authors.initials: DM
authors.lastname: Ney
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D002364:Caseins / Q000494:pharmacology / Q000627:therapeutic use*; D018753:Diet, Protein-Restricted; D055119:Elastic Modulus / Q000187:drug effects; D005260:Female; D005269:Femur / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D010649:Phenylalanine / Q000378:metabolism*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics*; D010661:Phenylketonurias / Q000000981:diagnostic imaging / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*
chemical_list: D002364:Caseins; D010446:Peptide Fragments; C065989:caseinomacropeptide; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase