title: Use of imaging biomarkers to assess perfusion and glucose metabolism in the skeletal muscle of dystrophic mice.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease that affects 1 in 3500 boys. The disease is characterized by progressive muscle degeneration that results from mutations in or loss of the cytoskeletal protein, dystrophin, from the glycoprotein membrane complex, thus increasing the susceptibility of contractile muscle to injury. To date, disease progression is typically assessed using invasive techniques such as muscle biopsies, and while there are recent reports of the use of magnetic resonance, ultrasound and optical imaging technologies to address the issue of disease progression and monitoring therapeutic intervention in dystrophic mice, our study aims to validate the use of imaging biomarkers (muscle perfusion and metabolism) in a longitudinal assessment of skeletal muscle degeneration/regeneration in two murine models of muscular dystrophy.
  
  
  METHODS
  Wild-type (w.t.) and dystrophic mice (weakly-affected mdx mice that are characterized by a point mutation in dystrophin; severely-affected mdx:utrn⁻/⁻ (udx) mice that lack functional dystrophin and are null for utrophin) were exercised three times a week for 30 minutes. To follow the progression of DMD, accumulation of ¹⁸F-FDG, a measure of glucose metabolism, in both wild-type and affected mice was measured with a small animal PET scanner (GE eXplore Vista). To assess changes in blood flow and blood volume in the hind limb skeletal muscle, mice were injected intravenously with a CT contrast agent, and imaged with a small animal CT scanner (GE eXplore Ultra).
  
  
  RESULTS
  In hind limb skeletal muscle of both weakly-affected mdx mice and in severely-affected udx mice, we demonstrate an early, transient increase in both ¹⁸F-FDG uptake, and in blood flow and blood volume. Histological analysis of H&E-stained tissue collected from parallel littermates demonstrates the presence of both inflammatory infiltrate and centrally-located nuclei, a classic hallmark of myofibrillar regeneration. In both groups of affected mice, the early transient response was succeeded by a progressive decline in muscle perfusion and metabolism; this was also evidenced histologically.
  
  
  CONCLUSIONS
  The present study demonstrates the utility of non-invasive imaging biomarkers in characterizing muscle degeneration/regeneration in murine models of DMD. These techniques may now provide a promising alternative for assessing both disease progression and the efficacy of new therapeutic treatments in patients.
authors.affiliation: Imaging Program, Lawson Health Research Institute, 268 Grosvenor St., London N6A4V2, Canada.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Ahmad
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.forename: Robert
authors.initials: R
authors.lastname: Grange
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hadway
authors.forename: Savita
authors.initials: S
authors.lastname: Dhanvantari
authors.forename: David
authors.initials: D
authors.lastname: Hill
authors.forename: Ting-Yim
authors.initials: TY
authors.lastname: Lee
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D004195:Disease Models, Animal; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods; D011237:Predictive Value of Tests; D012039:Regional Blood Flow / Q000502:physiology*; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose