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Skeletal Muscle Degeneration and Regeneration after Femoral Artery Ligation in Mice: Monitoring with Diffusion MR Imaging¹

¹ From the Biomedical NMR Group, Department of Biomedical Engineering, Eindhoven University of Technology, Den Dolech 2, 5612 AZ, Eindhoven, the Netherlands (A.M.H., G.J.S., G.S.v.B., K.N.); and the Nutrition and Toxicology Research Institute (NUTRIM), Department of Movement Sciences, Maastricht University, Maastricht, the Netherlands (M.R.D.). Received March 17, 2006; revision requested May 18; revision received July 13; final version accepted September 8. Address correspondence to K.N. (e-mail: k.nicolay{at}tue.nl).

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (156K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (174K): [in this window] [in a new window] [Download PPT slide]   Figure 1d: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 1e: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (143K): [in this window] [in a new window] [Download PPT slide]   Figure 1f: Histologic specimens obtained from different regions of the tibialis anterior at different time points in the ligation model illustrate changes in tissue over time: (a) central region before ligation; (b) central region immediately after ligation; (c) central region 3 days after ligation; (d) peripheral region 3 days after ligation; (e) central region 10 days after ligation, with three zones—degenerating zone (near tendon sheet [*]), inflammatory zone, and regenerating zone (small dotted lines); and (f) central region 21 days after ligation. Muscle recovery generally progressed from the outer regions to the central regions. Given examples (from different mice) are representative of all mice and all muscles, although the time course of recovery can vary between mice and between muscles. Muscles with a large cross-sectional area needed more time to recover than did smaller muscles. Arrows in a point to peripheral nuclei. In b–e, long black arrows point to rounder and/or swollen myocytes. In d and e, short black arrows point to inflammatory cells. In e and f, white arrows point to central nuclei. All slices were stained simultaneously with Gomori trichrome; therefore, differences in color did not originate from staining artifacts. Green color indicates collagen. (Original magnification, x10.)

View larger version (60K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Representative parametric images obtained in one mouse at different times (immediately [A] and days 3 [B], 10 [C], and 21 [D]) after right femoral artery ligation. On all images, the ligated limb is on the left. Image sections were obtained approximately centrally through the limb. ADC (values in x10–3 mm2/sec) and FA maps were derived from diffusion-weighted spin-echo MR (1500/30, b = 0 sec/mm2 or 572 sec/mm2) measurements. T2 maps (values in milliseconds) were derived from multiecho spin-echo MR (4000/13.3–79.8) measurements. The limbs appear flattened as a consequence of positioning, and the cross-sectional position of both limbs varied.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Changes in MR indexes before and as a result of femoral artery ligation. Data are mean values (for all mice) of the modus of the frequency distributions for three sections through the limb. ADC, 1, 2, and 3 (in x10–3 mm2/sec); T2 (in milliseconds); and FA values are shown. = ligated limb, = nonligated limb. Error bars represent standard deviations. * = P < .05, ** = P < .01, and *** = P < .001 for comparison of ligated versus nonligated limbs. The temporal evolution of the MR indexes in each limb indicated significant effects in the ligated limb (P < .001 for T2, 1, 2, and 3; P = .007 for ADC). In the nonligated limb, the temporal evolution was significant for 1 (P < .001), 2 (P < .001), 3 (P = .047), and ADC (P < .001), but not for T2 (P = .815) or FA (P = .284). The temporal evolutions of all indexes were different between the ligated and nonligated limbs (P < .001).

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 4a: Color plot of the orientation of the eigenvectors, for the mouse and image section shown in Figure 2, (a) immediately after femoral artery ligation; (b) 3 days after ligation, when all eigenvalues were increased; (c) 10 days after ligation; and (d) 21 days after ligation. A change in eigenvector orientation after 3 days was observed in half the mice. The effects were more pronounced for some animals, which had more pixels with changed orientation. At day 10, a region of changed orientation was still present in the gastrocnemius. This region corresponded to the location of increased ADC (Fig 2). The eigenvector orientations were color coded as follows: Blue indicated out of plane; green, top to bottom; and red, left to right.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 4b: Color plot of the orientation of the eigenvectors, for the mouse and image section shown in Figure 2, (a) immediately after femoral artery ligation; (b) 3 days after ligation, when all eigenvalues were increased; (c) 10 days after ligation; and (d) 21 days after ligation. A change in eigenvector orientation after 3 days was observed in half the mice. The effects were more pronounced for some animals, which had more pixels with changed orientation. At day 10, a region of changed orientation was still present in the gastrocnemius. This region corresponded to the location of increased ADC (Fig 2). The eigenvector orientations were color coded as follows: Blue indicated out of plane; green, top to bottom; and red, left to right.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 4c: Color plot of the orientation of the eigenvectors, for the mouse and image section shown in Figure 2, (a) immediately after femoral artery ligation; (b) 3 days after ligation, when all eigenvalues were increased; (c) 10 days after ligation; and (d) 21 days after ligation. A change in eigenvector orientation after 3 days was observed in half the mice. The effects were more pronounced for some animals, which had more pixels with changed orientation. At day 10, a region of changed orientation was still present in the gastrocnemius. This region corresponded to the location of increased ADC (Fig 2). The eigenvector orientations were color coded as follows: Blue indicated out of plane; green, top to bottom; and red, left to right.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 4d: Color plot of the orientation of the eigenvectors, for the mouse and image section shown in Figure 2, (a) immediately after femoral artery ligation; (b) 3 days after ligation, when all eigenvalues were increased; (c) 10 days after ligation; and (d) 21 days after ligation. A change in eigenvector orientation after 3 days was observed in half the mice. The effects were more pronounced for some animals, which had more pixels with changed orientation. At day 10, a region of changed orientation was still present in the gastrocnemius. This region corresponded to the location of increased ADC (Fig 2). The eigenvector orientations were color coded as follows: Blue indicated out of plane; green, top to bottom; and red, left to right.

View larger version (96K): [in this window] [in a new window] [Download PPT slide]   Figure 5: Comparison of MR and histologic findings in a mouse that still had considerable femoral artery damage after 10 days. A, T2 (0–60 msec), B, 3 ([0–2.1] x 10–3 mm2/sec), and, C, FA (0.1–0.7) maps, and, D, clustered MR image based on 3, FA, and T2 values are shown. Red represents high diffusivity; blue, high T2; and light blue, the highest T2. E, Histologic specimen from the same limb at an approximately corresponding cross section. For display purposes, the red and blue channels of the red/green/blue image (E) were enhanced (with image-processing tools) relative to the green channel. F, Histologic specimen from central region of tibialis anterior (area outlined by dotted-line rectangle in E) has high ADC and swollen cells. The locations of the blue regions in D are similar to the locations of the blue areas in E. G, Histologic specimen from the gastrocnemius (area outlined by solid-line rectangle in E) has high T2 and multiple inflammatory cells and collagen. Other mice had similar corresponding clustered image and histologic findings. (Gomori trichrome stain; original magnification, x40.)

View larger version (45K): [in this window] [in a new window] [Download PPT slide]   Figure 6a: Clusters of MR index data obtained (a) immediately, (b) 3 days, (c) 10 days, and (d) 21 days after ligation. The clusters are based on 3, FA, and T2 values and were obtained from the data presented in Figure 2. The clusters are representative of the data sets for the other mice. Mean values for all mice are given in the Table. In general, green, pink, and yellow represent normal values; red represents high diffusivity; blue represents high T2; light blue represents the highest T2; and orange represents reduced diffusivity.

View larger version (46K): [in this window] [in a new window] [Download PPT slide]   Figure 6b: Clusters of MR index data obtained (a) immediately, (b) 3 days, (c) 10 days, and (d) 21 days after ligation. The clusters are based on 3, FA, and T2 values and were obtained from the data presented in Figure 2. The clusters are representative of the data sets for the other mice. Mean values for all mice are given in the Table. In general, green, pink, and yellow represent normal values; red represents high diffusivity; blue represents high T2; light blue represents the highest T2; and orange represents reduced diffusivity.

View larger version (47K): [in this window] [in a new window] [Download PPT slide]   Figure 6c: Clusters of MR index data obtained (a) immediately, (b) 3 days, (c) 10 days, and (d) 21 days after ligation. The clusters are based on 3, FA, and T2 values and were obtained from the data presented in Figure 2. The clusters are representative of the data sets for the other mice. Mean values for all mice are given in the Table. In general, green, pink, and yellow represent normal values; red represents high diffusivity; blue represents high T2; light blue represents the highest T2; and orange represents reduced diffusivity.

View larger version (48K): [in this window] [in a new window] [Download PPT slide]   Figure 6d: Clusters of MR index data obtained (a) immediately, (b) 3 days, (c) 10 days, and (d) 21 days after ligation. The clusters are based on 3, FA, and T2 values and were obtained from the data presented in Figure 2. The clusters are representative of the data sets for the other mice. Mean values for all mice are given in the Table. In general, green, pink, and yellow represent normal values; red represents high diffusivity; blue represents high T2; light blue represents the highest T2; and orange represents reduced diffusivity.