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Use of imaging biomarkers to assess perfusion and glucose metabolism in the skeletal muscle of dystrophic mice.

Ahmad N, Welch I, Grange R, Hadway J, Dhanvantari S, Hill D, Lee TY, Hoffman LM - BMC Musculoskelet Disord (2011)

Bottom Line: 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.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.The present study demonstrates the utility of non-invasive imaging biomarkers in characterizing muscle degeneration/regeneration in murine models of DMD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Imaging Program, Lawson Health Research Institute, 268 Grosvenor St., London N6A4V2, Canada.

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 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.

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Related in: MedlinePlus

Normalized blood flow, NBF (a) and normalized blood volume, NBV (b) in hind limb muscle (HL). Data was collected over a 14-16 week period from age 6 to 20-22 in exercised w.t. (W.T.-Ex), non-exercised mdx (MDX-N.E.), exercised mdx (MDX-Ex) and non-exercised udx (UDX-N.E.) mice. Plotted values are means and standard deviations of NBF and NBV of surviving mice from each group. Significant differences (p <0.05) were found at age 8 and 20 between: W.T.-Ex and MDX-N.E. (μ), W.T.-Ex and MDX-Ex (*), W.T.-Ex and UDX-N.E.(ψ), MDX-N.E. and UDX-N.E. (≏), MDX-N.E. and MDX-Ex (ϕ).
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Figure 3: Normalized blood flow, NBF (a) and normalized blood volume, NBV (b) in hind limb muscle (HL). Data was collected over a 14-16 week period from age 6 to 20-22 in exercised w.t. (W.T.-Ex), non-exercised mdx (MDX-N.E.), exercised mdx (MDX-Ex) and non-exercised udx (UDX-N.E.) mice. Plotted values are means and standard deviations of NBF and NBV of surviving mice from each group. Significant differences (p <0.05) were found at age 8 and 20 between: W.T.-Ex and MDX-N.E. (μ), W.T.-Ex and MDX-Ex (*), W.T.-Ex and UDX-N.E.(ψ), MDX-N.E. and UDX-N.E. (≏), MDX-N.E. and MDX-Ex (ϕ).

Mentions: Absolute values of muscle perfusion (BF and BV), and glucose metabolic rate (SUV) measured at baseline for w.t., non-exercised mdx, exercised mdx and udx mice are provided in Table 1. As illustrated in Figure 3, normalized blood flow (NBF) and blood volume (NBV) in the HL musculature of healthy exercised w.t. mice did not change significantly from the initiation of the study at baseline to its termination. In each of the other 3 experimental groups, however, both NBF and NBV peaked 2 weeks post-baseline (8 weeks of age); specifically, mice in the non-exercised mdx group, the exercised mdx group, and the udx group exhibited an 18%, 38% and 42% increase in NBF above baseline, respectively (P < 0.05). Each experimental group exhibited similar changes in NBV, with a 40%, 79% and 97% increase above baseline observed in non-exercised mdx, exercised mdx and udx mice, respectively (P < 0.05). Significant differences in NBF and NBV were also observed between both mdx groups and the udx group, between non-exercised mdx and their exercised litter mates, and between all 3 groups and w.t. mice (P < 0.05).


Use of imaging biomarkers to assess perfusion and glucose metabolism in the skeletal muscle of dystrophic mice.

Ahmad N, Welch I, Grange R, Hadway J, Dhanvantari S, Hill D, Lee TY, Hoffman LM - BMC Musculoskelet Disord (2011)

Normalized blood flow, NBF (a) and normalized blood volume, NBV (b) in hind limb muscle (HL). Data was collected over a 14-16 week period from age 6 to 20-22 in exercised w.t. (W.T.-Ex), non-exercised mdx (MDX-N.E.), exercised mdx (MDX-Ex) and non-exercised udx (UDX-N.E.) mice. Plotted values are means and standard deviations of NBF and NBV of surviving mice from each group. Significant differences (p <0.05) were found at age 8 and 20 between: W.T.-Ex and MDX-N.E. (μ), W.T.-Ex and MDX-Ex (*), W.T.-Ex and UDX-N.E.(ψ), MDX-N.E. and UDX-N.E. (≏), MDX-N.E. and MDX-Ex (ϕ).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3141608&req=5

Figure 3: Normalized blood flow, NBF (a) and normalized blood volume, NBV (b) in hind limb muscle (HL). Data was collected over a 14-16 week period from age 6 to 20-22 in exercised w.t. (W.T.-Ex), non-exercised mdx (MDX-N.E.), exercised mdx (MDX-Ex) and non-exercised udx (UDX-N.E.) mice. Plotted values are means and standard deviations of NBF and NBV of surviving mice from each group. Significant differences (p <0.05) were found at age 8 and 20 between: W.T.-Ex and MDX-N.E. (μ), W.T.-Ex and MDX-Ex (*), W.T.-Ex and UDX-N.E.(ψ), MDX-N.E. and UDX-N.E. (≏), MDX-N.E. and MDX-Ex (ϕ).
Mentions: Absolute values of muscle perfusion (BF and BV), and glucose metabolic rate (SUV) measured at baseline for w.t., non-exercised mdx, exercised mdx and udx mice are provided in Table 1. As illustrated in Figure 3, normalized blood flow (NBF) and blood volume (NBV) in the HL musculature of healthy exercised w.t. mice did not change significantly from the initiation of the study at baseline to its termination. In each of the other 3 experimental groups, however, both NBF and NBV peaked 2 weeks post-baseline (8 weeks of age); specifically, mice in the non-exercised mdx group, the exercised mdx group, and the udx group exhibited an 18%, 38% and 42% increase in NBF above baseline, respectively (P < 0.05). Each experimental group exhibited similar changes in NBV, with a 40%, 79% and 97% increase above baseline observed in non-exercised mdx, exercised mdx and udx mice, respectively (P < 0.05). Significant differences in NBF and NBV were also observed between both mdx groups and the udx group, between non-exercised mdx and their exercised litter mates, and between all 3 groups and w.t. mice (P < 0.05).

Bottom Line: 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.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.The present study demonstrates the utility of non-invasive imaging biomarkers in characterizing muscle degeneration/regeneration in murine models of DMD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Imaging Program, Lawson Health Research Institute, 268 Grosvenor St., London N6A4V2, Canada.

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 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.

Show MeSH
Related in: MedlinePlus