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• W2511734478 abstract "Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization–reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green–enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized–reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green–enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo. Muscle damage is currently assessed through methods such as muscle biopsy, serum biomarkers, functional testing, and imaging procedures, each with its own inherent limitations, and a pressing need for a safe, repeatable, inexpensive, and noninvasive modality to assess the state of muscle health remains. Our aim was to develop and assess near-infrared (NIR) optical imaging as a novel noninvasive method of detecting and quantifying muscle damage. An immobilization–reambulation model was used for inducing muscle damage and recovery in the lower hindlimbs in mice. Confirmation of muscle damage was obtained using in vivo indocyanine green–enhanced NIR optical imaging, magnetic resonance imaging, and ex vivo tissue analysis. The soleus of the immobilized–reambulated hindlimb was found to have a greater amount of muscle damage compared to that in the contralateral nonimmobilized limb, confirmed by in vivo indocyanine green–enhanced NIR optical imaging (3.86-fold increase in radiant efficiency), magnetic resonance imaging (1.41-fold increase in T2), and an ex vivo spectrophotometric assay of indocyanine green uptake (1.87-fold increase in normalized absorbance). Contrast-enhanced NIR optical imaging provides a sensitive, rapid, and noninvasive screening method that can be used for imaging and quantifying muscle damage and recovery in vivo. Muscle damage is an important and unavoidable outcome of many pathologic states, such as muscular dystrophies, inflammatory myopathies, and physical trauma. Several preclinical models have been developed to induce acute muscle damage, including eccentric loading,1Armstrong R.B. Ogilvie R.W. Schwane J.A. Eccentric exercise-induced injury to rat skeletal muscle.J Appl Physiol Respir Environ Exerc Physiol. 1983; 54: 80-93PubMed Google Scholar, 2Clarkson P.M. Hubal M.J. Exercise-induced muscle damage in humans.Am J Phys Med Rehabil. 2002; 81: S52-S69Crossref PubMed Scopus (967) Google Scholar, 3Clarkson P.M. Byrnes W.C. McCormick K.M. Turcotte L.P. White J.S. Muscle soreness and serum creatine kinase activity following isometric, eccentric, and concentric exercise.Int J Sports Med. 1986; 7: 152-155Crossref PubMed Scopus (191) Google Scholar, 4Ploutz-Snyder L.L. Tesch P.A. Hather B.M. Dudley G.A. Vulnerability to dysfunction and muscle injury after unloading.Arch Phys Med Rehabil. 1996; 77: 773-777Abstract Full Text PDF PubMed Scopus (48) Google Scholar, 5Proske U. Morgan D.L. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications.J Physiol. 2001; 537: 333-345Crossref PubMed Scopus (911) Google Scholar immobilization-reloading,6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar and myotoxin injection.7Gutiérrez J.M. Ownby C.L. Skeletal muscle degeneration induced by venom phospholipases A2: insights into the mechanisms of local and systemic myotoxicity.Toxicon. 2003; 42: 915-931Crossref PubMed Scopus (333) Google Scholar, 8Lomonte B. Gutiérrez J.M. A new muscle damaging toxin, myotoxin II, from the venom of the snake Bothrops asper (terciopelo).Toxicon. 1989; 27: 725-733Crossref PubMed Scopus (196) Google Scholar, 9Lomonte B. Tarkowski A. Hanson L.A. Host response to Bothrops asper snake venom. Analysis of edema formation, inflammatory cells, and cytokine release in a mouse model.Inflammation. 1993; 17: 93-105Crossref PubMed Scopus (215) Google Scholar, 10Lomonte B. Angulo Y. Calderón L. An overview of lysine-49 phospholipase A2 myotoxins from Crotalid snake venoms and their structural determinants of myotoxic action.Toxicon. 2003; 42: 885-901Crossref PubMed Scopus (259) Google Scholar In particular, reloading of muscle following unloading has demonstrated an ability to robustly induce eccentric loading muscle damage.4Ploutz-Snyder L.L. Tesch P.A. Hather B.M. Dudley G.A. Vulnerability to dysfunction and muscle injury after unloading.Arch Phys Med Rehabil. 1996; 77: 773-777Abstract Full Text PDF PubMed Scopus (48) Google Scholar, 5Proske U. Morgan D.L. Muscle damage from eccentric exercise: mechanism, mechanical signs, adaptation and clinical applications.J Physiol. 2001; 537: 333-345Crossref PubMed Scopus (911) Google Scholar, 6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar, 11Kasper C.E. Sarcolemmal disruption in reloaded atrophic skeletal muscle.J Appl Physiol (1985). 1995; 79: 607-614PubMed Google Scholar Reloading, in the form of reambulation following immobilization, has demonstrated ultrastructural perturbations to muscle consistent with muscle damage.6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar, 11Kasper C.E. Sarcolemmal disruption in reloaded atrophic skeletal muscle.J Appl Physiol (1985). 1995; 79: 607-614PubMed Google Scholar, 12Krippendorf B.B. Riley D.A. Temporal changes in sarcomere lesions of rat adductor longus muscles during hindlimb reloading.Anat Rec. 1994; 238: 304-310Crossref PubMed Scopus (40) Google Scholar, 13Vijayan K. Thompson J.L. Riley D.A. Sarcomere lesion damage occurs mainly in slow fibers of reloaded rat adductor longus muscles.J Appl Physiol (1985). 1998; 85: 1017-1023PubMed Google Scholar Compromised sarcolemmal membranes release muscle enzymes such as creatine kinase while passively taking up large serum proteins and markers such as Evans blue dye (EBD).14Hamer P.W. McGeachie J.M. Davies M.J. Grounds M.D. Evans Blue Dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability.J Anat. 2002; 200: 69-79Crossref PubMed Scopus (221) Google Scholar Muscle pathology has been measured by a number of techniques, all of which possess their own inherent limitations. These techniques include muscle biopsy, serology, functional measures, and imaging methods. Muscle biopsy, although the most direct measure of pathology, has a capacity too limited to be considered a longitudinal measure of muscle pathology due to the necessity of repeated sample collections. Although serology and functional testing provide a proxy to the overall state of muscle health, they fail to sensitively localize pathology, instead providing information regarding the general health of all muscles in the body, and are complicated by the changes in lean body mass typically associated with myopathy. Magnetic resonance imaging (MRI) has evolved as a noninvasive method of detecting and quantifying muscle pathology6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar, 15Dunn J.F. Zaim-Wadghiri Y. Quantitative magnetic resonance imaging of the mdx mouse model of Duchenne muscular dystrophy.Muscle Nerve. 1999; 22: 1367-1371Crossref PubMed Scopus (47) Google Scholar, 16Frimel T.N. Kapadia F. Gaidosh G.S. Li Y. Walter G.A. Vandenborne K. A model of muscle atrophy using cast immobilization in mice.Muscle Nerve. 2005; 32: 672-674Crossref PubMed Scopus (46) Google Scholar, 17Kobayashi Y.M. Rader E.P. Crawford R.W. Iyengar N.K. Thedens D.R. Faulkner J.A. Parikh S.V. Weiss R.M. Chamberlain J.S. Moore S.A. Campbell K.A. Sarcolemma-localized nNOS is required to maintain activity after mild exercise.Nature. 2008; 456: 511-515Crossref PubMed Scopus (227) Google Scholar, 18Vohra R.S. Mathur S. Bryant N.D. Forbes S. Vandenborne K. Walter G.A. Age-related T2 changes in hindlimb muscles of mdx mice.Muscle Nerve. 2016; 53: 84-90Crossref Scopus (19) Google Scholar, 19Walter G. Cordier L. Bloy D. Lee Sweeney H. Noninvasive monitoring of gene correction in dystrophic muscle.Magn Reson Med. 2005; 54: 1369-1376Crossref PubMed Scopus (55) Google Scholar but has several limitations, such as cost; speed of operations; and contraindications in subjects with metallic implants, claustrophobia, and compliance issues.20Brockmann M.A. Kemmling A. Groden C. Current issues and perspectives in small rodent magnetic resonance imaging using clinical MRI scanners.Methods. 2007; 43: 79-87Crossref PubMed Scopus (56) Google Scholar An attractive possible alternative would be the use of clinically approved fluorescent optical contrast agents for imaging muscle damage in vivo, similar to those currently used for conventional histologic measurements.21Baudy A.R. Sali A. Jordan S. Kesari A. Johnston H.K. Hoffman E.P. Nagaraju K. Non-invasive Optical Imaging of Muscle Pathology in mdx Mice Using Cathepsin Caged Near-Infrared Imaging.Mol Imaging Biol. 2011; 13: 462-470Crossref Scopus (25) Google Scholar, 22Inage K. Sakuma Y. Yamauchi K. Suganami A. Orita S. Kubota G. Oikawa Y. Sainoh T. Sato J. Fujimoto K. Shiga Y. Takahashi K. Ohtori S. Tamura T. Longitudinal evaluation of local muscle conditions in a rat model of gastrocnemius muscle injury using an in vivo imaging system.J Orthop Res. 2015; 33: 1034-1038Crossref Scopus (7) Google Scholar, 23Kossodo S. Pickarski M. Lin S.A. Gleason A. Gaspar R. Buono C. Ho G. Blusztajn A. Cuneo G. Zhang J. Jensen J. Hargreaves R. Coleman P. Hartman G. Rajopadhye M. Duong L.Y. Sur C. Yared W. Peterson J. Bohumil B. Dual in vivo quantification of integrin-targeted and protease-activated agents in cancer using fluorescence molecular tomography (FMT).Mol Imaging Biol. 2010; 12: 488-499Crossref PubMed Scopus (74) Google Scholar In preclinical models of disease, fluorescent optical imaging is a technique widely used for detecting pathology by fluorescent dyes, proteins, and conjugates.24Frangioni J.V. In vivo near-infrared fluorescence imaging.Curr Opin Chem Biol. 2003; 7: 626-634Crossref PubMed Scopus (2147) Google Scholar, 25Tan Y. Jiang H. Diffuse optical tomography guided quantitative fluorescence molecular tomography.Appl Opt. 2008; 47: 2011-2016Crossref PubMed Scopus (71) Google Scholar By using optical imaging in the near-infrared (NIR) range (700 to 1000 nm), two primary advantages exist over conventional fluorophores that operate at shorter wavelengths: deeper photon penetration within tissues and minimal tissue autofluorescence.24Frangioni J.V. In vivo near-infrared fluorescence imaging.Curr Opin Chem Biol. 2003; 7: 626-634Crossref PubMed Scopus (2147) Google Scholar, 26Weissleder R. A clearer vision for in vivo imaging.Nat Biotechnol. 2001; 19: 316-317Crossref PubMed Scopus (3116) Google Scholar, 27Weissleder R. Ntziachristos V. Shedding light onto live molecular targets.Nat Med. 2003; 9: 123-128Crossref PubMed Scopus (1704) Google Scholar When imaging in the NIR range, penetration of signal can overcome some of the scattering encountered with other fluorescent imaging techniques at shorter wavelengths.28Ntziachristos V. Ripoll J. Wang L.V. Weissleder R. Looking and listening to light: the evolution of whole-body photonic imaging.Nat Biotechnol. 2005; 23: 313-320Crossref PubMed Scopus (1424) Google Scholar The first, and still the only, NIR fluorescent contrast agent approved by the US Food and Drug Administration (FDA) is indocyanine green (ICG).29Alford R. Simpson H.M. Duberman J. Hill G.C. Ogawa M. Regino C. Kobayashi H. Choyke P.L. Toxicity of organic fluorophores used in molecular imaging: literature review.Mol Imaging. 2009; 8: 341-354PubMed Google Scholar ICG is primarily and rapidly bound to albumin and lipoproteins within the circulation and thus acts as a blood-pooling NIR fluorescent agent, highlighting vasculature in several systems.30Kobayashi S. Ishikawa T. Tanabe J. Moroi J. Suzuki A. Quantitative cerebral perfusion assessment using microscope-integrated analysis of intraoperative indocyanine green fluorescence angiography versus positron emission tomography in superficial temporal artery to middle cerebral artery anastomosis.Surg Neurol Int. 2014; 5: 135Crossref PubMed Scopus (15) Google Scholar, 31Raabe A. Beck J. Gerlach R. Zimmermann M. Seifert V. Near-infrared indocyanine green video angiography: a new method for intraoperative assessment of vascular flow.Neurosurgery. 2003; 52: 132-139Crossref PubMed Google Scholar Furthermore, through the enhanced permeation and retention effect, ICG passively accumulates in tumors, in a manner parallel to that of the MR contrast agent gadolinium.32Corlu A. Choe R. Durduran T. Rosen M.A. Schweiger M. Arridge S.R. Schnall M.D. Yodh A.G. Three-dimensional in vivo fluorescence diffuse optical tomography of breast cancer in humans.Opt Express. 2007; 15: 6696-6716Crossref PubMed Scopus (331) Google Scholar, 33Ntziachristos V. Yodh A.G. Schnall M. Chance B. Concurrent MRI and diffuse optical tomography of breast after indocyanine green enhancement.Proc Natl Acad Sci U S A. 2000; 97: 2767-2772Crossref PubMed Scopus (774) Google Scholar Despite its widespread use in imaging other organs, only conjugates of ICG have demonstrated the capability of imaging compromised muscle.22Inage K. Sakuma Y. Yamauchi K. Suganami A. Orita S. Kubota G. Oikawa Y. Sainoh T. Sato J. Fujimoto K. Shiga Y. Takahashi K. Ohtori S. Tamura T. Longitudinal evaluation of local muscle conditions in a rat model of gastrocnemius muscle injury using an in vivo imaging system.J Orthop Res. 2015; 33: 1034-1038Crossref Scopus (7) Google Scholar With this in mind, we hypothesized that clinical-grade ICG will behave similarly to EBD,14Hamer P.W. McGeachie J.M. Davies M.J. Grounds M.D. Evans Blue Dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability.J Anat. 2002; 200: 69-79Crossref PubMed Scopus (221) Google Scholar and accumulate in damaged muscle fibers, allowing for the quantification of muscle damage in a longitudinal and in vivo manner. Importantly, because access to preclinical fluorescent imaging is more ubiquitous than is access to MRI, ICG-enhanced optical imaging may be a suitable complement to more expensive and time-consuming MRI scanners in preclinical muscle pathology studies. In this article we assessed whether ICG-enhanced NIR optical imaging is capable of measuring acute muscle damage and recovery in a targeted deep hindlimb muscle in mice. To validate the NIR optical imaging findings, direct comparisons to MR measures of muscle damage and ex vivo tissue assessments were performed. All studies were approved by the University of Florida's institutional animal care and use committee, and the research was performed at the University of Florida, Gainesville, FL. Male C57BL/6J mice (n = 60) were bred in-house through the University of Florida's Animal Care Services and were 6 to 8 weeks of age during experimentation. Mice were housed in a facility regulated by the Association for Assessment and Accreditation of Laboratory Animal Care (12 hours light/dark, 22°C, 42% humidity) and provided food ad libitum. Additionally, a transgenic dough diet (BioServ, Flemington, NJ) was provided for the mice at the base of the cages during the entire procedure to ensure that dietary needs were met during and after hindlimb immobilization. Right hindlimbs were immobilized in a plantar-flexed position, first by medical-grade paper tape, followed by plaster of Paris (OrthoTape, Blufton, SC), and finally an encompassing single layer of casting material (Patterson Medical, Warrenville, IL), as previously described.6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar, 16Frimel T.N. Kapadia F. Gaidosh G.S. Li Y. Walter G.A. Vandenborne K. A model of muscle atrophy using cast immobilization in mice.Muscle Nerve. 2005; 32: 672-674Crossref PubMed Scopus (46) Google Scholar The contralateral leg (nonimmobilized) served as each mouse's own control. Mice were checked daily for abrasion wounds as a result of the casting procedure, and animal weight was monitored. After 2 weeks of immobilization, casts were removed, and the animals were allowed to undergo free-cage ambulation. Data (MRI, NIR optical imaging, and tissue assessment) were acquired at 0, 1, 2, 3, 5, and 7 days following the removal of casts (n = 10 per time point). Eighteen hours before sacrifice, 1% filter-sterilized EBD (Sigma-Aldrich, St. Louis, MO) in phosphate-buffered saline (0.1 g/mL per mg i.p.) was administered to the mice as previously described.14Hamer P.W. McGeachie J.M. Davies M.J. Grounds M.D. Evans Blue Dye as an in vivo marker of myofibre damage: optimising parameters for detecting initial myofibre membrane permeability.J Anat. 2002; 200: 69-79Crossref PubMed Scopus (221) Google Scholar One hour before NIR optical imaging, NirawaveC ICG (Miltenyi Biotech Inc., San Diego, CA) was administered to the mice according to the package insert (1 mg ICG/kg body weight i.v.). It was determined that a steady signal was maintained between 30 minutes and 3 hours after injection (data not shown); thus, NIR optical imaging data were collected during this window of time following injections of ICG contrast dye. Mice were anesthetized using an oxygen and isoflurane mixture (3% induction; 0.75% to 1% maintenance) and two-dimensional NIR optical imaging was performed using an In Vivo Fluorescence Imager (PerkinElmer, Waltham, MA). Image capture took, on average, <1 minute/mouse. Acquired images were analyzed using Living Image software version 4.0 (PerkinElmer) on the same In Vivo Fluorescence Imager. Data acquisition was controlled for binning, F/stop, subject height, and field of view. Additionally, normalization to the exposure time of the camera was manually performed for each image. Excitation and emission wavelengths were 745 and 820 nm, respectively. Regions of interest were carefully drawn over both the immobilized and nonimmobilized lower hindlimbs, and total radiant efficiency (p/cm2/sr)/(μW/cm2) within the designated regions of interest was recorded by the In Vivo Fluorescence Imager. MRI was performed in a 4.7 T horizontal 22.5-cm bore magnet (Agilent, Santa Clara, CA) immediately following NIR optical imaging. Animals were anesthetized using an oxygen and isoflurane mixture (3% induction; 0.75% to 1% maintenance) and were kept warm with a heated water tubing system for the duration of all MR procedures. Respiratory rate and temperature were monitored (Small Animal Instruments, Stony Brook, NY) throughout the scans to ensure adequate physiological maintenance while the animals were under anesthesia, and anesthesia was appropriately adjusted to maintain adequate vital sign values. In all, MRI scans took approximately 30 minutes to perform. The lower hindlimbs of the mice were inserted into a custom-built solenoid 1H coil (200 MHz; 2.0-cm internal diameter). To obtain correct positioning of all subsequent scans, localizer images in three orthogonal planes were acquired using a gradient echo sequence (repetition time = 30 ms; echo time = 5 ms; slice thickness = 2 mm; slice number = 3 per plane; acquisition matrix = 128 × 128; signal averages = 1). Axial proton T2-weighted multislice MRIs were acquired along the length of all lower hindlimbs (repetition time = 2000 ms; echo time = 14 and 40 ms; field of view = 10 × 20 mm2; slice thickness = 1 mm; slice number = 12; acquisition matrix = 128 × 256; signal averages = 2). Signal-to-noise ratios were approximately 21:1 and 7.4:1 at echo times of 14 and 40 ms, respectively. MRIs were converted from raw Varian format to digital imaging and communications in medicine files for analysis. Series of three consecutive slices were used for quantifying MRI-T2 measurements, beginning approximately 6 mm distal to the tibial plateau as the anatomic reference point, ensuring that consistent measurements were performed. Regions of interest around the soleus, gastrocnemius, and tibialis anterior muscles were drawn using OsiriX software version 5.0.2 (OsiriX, Geneva, Switzerland) to calculate signal intensity, and the mean T2 relaxation times of each of the designated muscles was calculated from the pixel signal intensity at echo times of 14 and 40 ms, as previously described.6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar, 16Frimel T.N. Kapadia F. Gaidosh G.S. Li Y. Walter G.A. Vandenborne K. A model of muscle atrophy using cast immobilization in mice.Muscle Nerve. 2005; 32: 672-674Crossref PubMed Scopus (46) Google Scholar, 18Vohra R.S. Mathur S. Bryant N.D. Forbes S. Vandenborne K. Walter G.A. Age-related T2 changes in hindlimb muscles of mdx mice.Muscle Nerve. 2016; 53: 84-90Crossref Scopus (19) Google Scholar, 34Mathur S. Vohra R.S. Germain S.A. Forbes S. Bryant N.D. Vandenborne K. Walter G.A. Changes in muscle T2 and tissue damage after downhill running in mdx Mice.Muscle Nerve. 2011; 43: 878-886Crossref PubMed Scopus (59) Google Scholar Mice were sacrificed the day following NIR optical imaging and MR data capture. At 15 to 18 hours before animal sacrifice, mice were administered EBD and ICG. Muscles (tibialis anterior, soleus, and gastrocnemius) were carefully dissected, fixed in optimal cutting temperature medium at resting length, and immediately frozen in precooled isopentane, then liquid nitrogen, and stored at −80°C. Morphologic features of captured tissue sections were assessed by hematoxylin and eosin staining, and uptake of EBD into fibers was determined by fluorescent microscopy. To determine the percentage of muscle that was EBD positive, fibers that stained positive for EBD were manually counted and divided by the total number of fibers in each muscle's cross-sectional area. Whereas muscle fiber accumulation of EBD could be easily visualized using standard epifluorescence of cryosectioned muscle, attempts to directly visualize ICG in tissue sections were unsuccessful despite the use of a high-sensitivity back-thinned charge coupled device (catalog number EM-CCD C9100-13; Hamamatsu, Hamamatsu City, Japan) due to ICG concentration limitations. Therefore, spectrophotometric quantification of ICG and EBD accumulation in individual muscles (soleus, gastrocnemius, and tibialis anterior) was performed as previously described.35Yaseen M.A. Yu J. Jung B. Wong M.S. Anvari B. Biodistribution of Encapsulated Indocyanine Green in Healthy Mice.Mol Pharm. 2009; 6: 1321-1332Crossref PubMed Scopus (91) Google Scholar In brief, muscles were pulverized in lyzing matrix D tubes (MP Biomedicals, Santa Ana, CA) in dimethyl sulfoxide (Sigma-Aldrich, St. Louis, MO), followed by centrifugation. The absorbance values of EBD and ICG were subsequently measured at 620 and 780 nm, respectively, on a SpectraMax 5 spectrophotometer (Molecular Devices, Sunnyvale, CA), and normalized to tissue weights for assessment of dye uptake. All statistical analyses were performed using Prism software version 6.0 (GraphPad, La Jolla, CA). Results are expressed as means ± SEM, unless otherwise stated. Significance levels were tested at an α level of 0.05. Noncasted hindlimbs served as the control for each individual animal. Two-way analysis of variance with planned Bonferroni correction was performed to compare both the duration of reambulation and the presence or absence of immobilization. Cohen's d values were calculated to determine effect sizes for comparing NIR optical imaging with MRI. A linear regression model was used for calculating the correlation between radiant efficiency, MRI-T2, and spectrophotometric data. Throughout the duration of the experiments, all mice were maintained at a body weight within 10% of preimmobilization weight, and three needed recasting because abrasive lesions had developed on the skin. In these rare cases, topical antibiotics were applied to address abrasive lesions, all with resolution. One mouse unexpectedly expired following data collection in the MR scanner and was not used in the data analysis. The single hindlimb casting procedures were otherwise well-tolerated through the duration of the experiments. Before the immobilization procedure, mice demonstrated minimal fluorescence distribution in both hindlimbs, and on comparison of preimmobilization and day-0 reambulated hindlimbs, no differences were observed between the immobilized and nonimmobilized hindlimbs (Figure 1A). Throughout the reambulation phase, radiant efficiency in the immobilized–reambulated hindlimbs significantly peaked by day 2 and was 3.86-fold higher than precasted values, followed by a return to baseline by day 7 (Figure 1). Interestingly, the contralateral hindlimbs also demonstrated an increase (2.45-fold) in total radiant efficiency between day 2 reambulation and precasted values, but this difference did not reach significance. NIR images are presented (Figure 1A), allowing for qualitative demonstration of the immobilized (right) versus nonimmobilized (left) hindlimbs. The quantitative assessment time course of total radiant efficiency throughout the week of reambulation is presented in Figure 1B. The total radiant efficiency values of the immobilized–reambulated hindlimbs on days 2 and 3 of reambulation were significantly different from those of the contralateral and preimmobilized hindlimbs and day 0 of the immobilized–reambulated limbs. Interestingly, the nonimmobilized hindlimbs demonstrated a subtle, nonsignificant increase in total radiant efficiency on the 2nd day of reambulation. Preimmobilization, both hindlimbs demonstrated homogenous contrast in all of the muscles on T2-weighted MRIs (Figure 2A). The soleus muscle of the immobilized–reambulated hindlimb demonstrated the greatest T2 changes, peaking at 2 days following cast removal (1.41-fold change increase in T2), and values were comparable to those from baseline by day 5 of the reambulation phase (Figure 2B). Interestingly, both the gastrocnemii and tibialis anterior muscles of the immobilized–reambulated hindlimbs demonstrated subtle, yet significant, differences in T2 changes (1.13- and 1.14-fold changes, respectively) compared with those of their contralateral nonimmobilized limbs at the initiation of reambulation, but these values were not significantly different from preimmobilization measures (Figure 2, C and D). Ex vivo assessment of tissue was used for confirming in vivo NIR optical imaging and MRI findings. The appearance of EBD accumulation at both the microscopic and macroscopic levels within the soleus muscles confirmed the well-established time course of damage and recovery during reloading following immobilization. EBD was minimally taken up into soleus muscle fibers immediately following cast removal (Figure 3A). Quantitative demonstration of dye uptake into the immobilized–reambulated and contralateral control solei are demonstrated in Figure 3B. The percentage of EBD-positive fibers in the gastrocnemius (Supplemental Figure S1) was elevated at day 3 relative to baseline values; the tibialis anterior (Supplemental Figure S2) demonstrated no significant changes in EBD-positive fibers throughout the reambulation period. By the 2nd day of reambulation, fibers of the immobilized–reambulated soleus appeared, with 47.1% ± 15.6% of the fibers being EBD positive in a checkerboard pattern. EBD uptake into the contralateral soleus was less, with 15.1% ± 6.3% of fibers the being EBD positive, but this value was not significantly different from that on day 0 in the soleus muscle in the same control limb. At the end of the reambulation week, EBD signal is again less visible with only 5.6% ± 2% and 1.6% ± 1.8% of the fibers being EBD positive for the immobilized–reambulated and control hindlimbs, respectively. Hematoxylin and eosin–stained sections of the immobilized and reambulated soleus at various time points throughout the week demonstrated the well-characterized histopathologic features of muscle damage, most noticeably on the 2nd day of reambulation.6Frimel T.N. Walter G.A. Gibbs J.D. Gaidosh G.S. Vandenborne K. Noninvasive monitoring of muscle damage during reloading following limb disuse.Muscle Nerve. 2005; 32: 605-612Crossref PubMed Scopus (34) Google Scholar At the peak of damage (day 2), widened extracellular spaces, decreased density of muscle fibers, and" @default.
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• W2511734478 title "Near-Infrared Optical Imaging Noninvasively Detects Acutely Damaged Muscle" @default.
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