The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships ...between non-contractile content and functional abilities.
Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed.
Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups.
Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we ...investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.
Genetic modifiers alter disease progression in both preclinical models and subjects with Duchenne muscular dystrophy (DMD). Using multiparametric magnetic resonance (MR) techniques, we compared the ...skeletal and cardiac muscles of two different dystrophic mouse models of DMD, which are on different genetic backgrounds, the C57BL/10ScSn-Dmdmdx (B10-mdx) and D2.B10-Dmdmdx (D2-mdx). The proton transverse relaxation constant (T2) using both MR imaging and spectroscopy revealed significant age-related differences in dystrophic skeletal and cardiac muscles as compared with their age-matched controls. D2-mdx muscles demonstrated an earlier and accelerated decrease in muscle T2 compared with age-matched B10-mdx muscles. Diffusion-weighted MR imaging indicated differences in the underlying muscle structure between the mouse strains. The fractional anisotropy, mean diffusion, and radial diffusion of water varied significantly between the two dystrophic strains. Muscle structural differences were confirmed by histological analyses of the gastrocnemius, revealing a decreased muscle fiber size and increased fibrosis in skeletal muscle fibers of D2-mdx mice compared with B10-mdx and control. Cardiac involvement was also detected in D2-mdx myocardium based on both decreased function and myocardial T2. These data indicate that MR parameters may be used as sensitive biomarkers to detect fibrotic tissue deposition and fiber atrophy in dystrophic strains.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To elucidate the reliability of MRI as a non-invasive tool for assessing in vivo muscle health and pathological amelioration in response to Losartan (Angiotensin II Type 1 receptor blocker) in DyW ...mice (mouse model for Laminin-deficient Congenital Muscular Dystrophy Type 1A).
Multiparametric MR quantifications along with histological/biochemical analyses were utilized to measure muscle volume and composition in untreated and Losartan-treated 7-week old DyW mice.
MRI shows that DyW mice have significantly less hind limb muscle volume and areas of hyperintensity that are absent in WT muscle. DyW mice also have significantly elevated muscle levels (suggestive of inflammation and edema). Muscle T2 returned to WT levels in response to Losartan treatment. When considering only muscle pixels without T2 elevation, DyW T2 levels are significantly lower than WT (suggestive of fibrosis) whereas Losartan-treated animals do not demonstrate this decrease in muscle T2. MRI measurements suggestive of elevated inflammation and fibrosis corroborate with increased Mac-1 positive cells as well as increased Picrosirius red staining/COL1a gene expression that is returned to WT levels in response to Losartan.
MRI is sensitive to and tightly corresponds with pathological changes in DyW mice and thus is a viable and effective non-invasive tool for assessing pathological changes.
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Lack of sarcolemma-localized neuronal nitric oxide synthase mu (nNOSμ) contributes to muscle damage and fatigue in dystrophic muscle. In this study, we examined the effects of compensating for lack ...of nNOSμ with a phosphodiesterase type 5 (PDE5) inhibitor in
mice following downhill running and endurance training. Dystrophic mice (
) were treated with sildenafil citrate and compared with untreated
and wild-type mice after an acute bout of downhill running and during a progressive low-intensity treadmill running program (5 days/wk, 4 wk). Magnetic resonance imaging (MRI) and spectroscopy (MRS) transverse relaxation time constant (T
) of hindlimb and forelimb muscles were measured as a marker of muscle damage after downhill running and throughout training. The MRI blood oxygenation level dependence (BOLD) response and
phosphorus MRS (
P-MRS) data were acquired after stimulated muscle contractions. After downhill running, the increase in T
was attenuated (
< 0.05) in treated
and wild-type mice compared with untreated
. During training, resting T
values did not change in wild-type and
mice from baseline values; however, the running distance completed during training was greater (
< 0.05) in treated
(>90% of target distance) and wild-type (100%) than untreated
(60%). The post-contractile BOLD response was greater (
< 0.05) in treated
that trained than untreated
, with no differences in muscle oxidative capacity, as measured by
P-MRS. Our findings indicate that PDE5 inhibition reduces muscle damage after a single bout of downhill running and improves performance during endurance training in dystrophic mice, possibly because of enhanced microvascular function.
This study examined the combined effects of PDE5 inhibition and exercise in dystrophic muscle using high-resolution magnetic resonance imaging and spectroscopy. Our findings demonstrated that sildenafil citrate reduces muscle damage after a single bout of downhill running, improves endurance-training performance, and enhances microvascular function in dystrophic muscle. Collectively, the results support the combination of exercise and PDE5 inhibition as a therapeutic approach in muscular dystrophies lacking nNOSμ.
Abstract Mathur S, Lott DJ, Senesac C, Germain SA, Vohra RS, Sweeney HL, Walter GA, Vandenborne K. Age-related differences in lower-limb muscle cross-sectional area and torque production in boys with ...Duchenne muscular dystrophy. Objective To examine the relationship between lower-extremity muscle cross-sectional area, muscle strength, specific torque, and age in ambulatory boys with Duchenne muscular dystrophy (DMD) compared with controls. Design Observational cross-sectional study. Setting University research setting. Participants Volunteer sample of boys with DMD (n=22) and healthy control boys (n=10), ages 5 through 14 years. Interventions Not applicable. Main Outcome Measures Maximal muscle cross-sectional area (CSAmax ) assessed by magnetic resonance imaging of quadriceps, plantarflexors (PFs) and dorsiflexors (DFs), peak isometric torque from dynamometry, and timed functional tests. Results The average CSAmax of the triceps surae muscle group was approximately 60% higher in boys with DMD compared with controls (39.1±13.6 cm2 vs 24.5±9.3 cm2 ; P =.002), while the tibialis anterior muscle showed age-appropriate increases in CSAmax . The increase in quadriceps CSAmax was also distinctly different in boys with DMD compared with controls. Specific torque (ie, peak torque/CSAmax ) was impaired in all 3 muscles groups, with the knee extensor (KE) and PF muscles showing 4-fold, and the DF muscles 2-fold, higher values in controls compared with boys with DMD. Large age-related gains in specific torque were observed in all 3 muscle groups of control subjects, which were absent in ambulatory boys with DMD. Correlations were observed between performance on functional tasks and quadriceps and PF torque production ( r =−.45 to −.57, P <.05), but not with DF strength. Conclusions Age-related changes in muscle cross-sectional area and specific torque production in lower-extremity muscles showed distinctly different patterns in the KE, PF, and DF muscles of boys with DMD compared with controls.
Pancreatic ductal adenocarcinomas are characterized by a complex and robust tumor microenvironment (TME) consisting of fibrotic tissue, excessive levels of hyaluronan (HA), and immune cells. We ...utilized quantitative multi-parametric magnetic resonance imaging (mp-MRI) methods at 14 Tesla in a genetically engineered KPC (
,
,
mouse model to assess the complex TME in advanced stages of tumor development. The whole tumor, excluding cystic areas, was selected as the region of interest for data analysis and subsequent statistical analysis. Pearson correlation was used for statistical inference. There was a significant correlation between tumor volume and T2 (r = -0.66), magnetization transfer ratio (MTR) (r = 0.60), apparent diffusion coefficient (ADC) (r = 0.48), and Glycosaminoglycan-chemical exchange saturation transfer (GagCEST) (r = 0.51). A subset of mice was randomly selected for histological analysis. There were positive correlations between tumor volume and fibrosis (0.92), and HA (r = 0.76); GagCEST and HA (r = 0.81); and MTR and CD31 (r = 0.48). We found a negative correlation between ADC low-b (perfusion) and Ki67 (r = -0.82). Strong correlations between mp-MRI and histology results suggest that mp-MRI can be used as a non-invasive tool to monitor the tumor microenvironment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ABSTRACT
Introduction
Magnetic resonance imaging (MRI) was used to monitor changes in the transverse relaxation time constant (T2) in lower hindlimb muscles of mdx mice at different ages.
Methods
...Young (5 weeks), adult (44 weeks), and old mdx (96 weeks), and age‐matched control mice were studied. Young mdx mice were imaged longitudinally, whereas adult and old mdx mice were imaged at a single time‐point.
Results
Mean muscle T2 and percent of pixels with elevated T2 were significantly different between mdx and control mice at all ages. In young mdx mice, mean muscle T2 peaked at 7–8 weeks and declined at 9–11 weeks. In old mdx mice, mean muscle T2 was decreased compared with young and adult mice, which could be attributed to fibrosis.
Conclusions
MRI captured longitudinal changes in skeletal muscle integrity of mdx mice. This information will be valuable for pre‐clinical testing of potential therapeutic interventions for muscular dystrophy. Muscle Nerve 53: 84–90, 2016
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this study, multi-parametric magnetic resonance imaging (MRI) was conducted to monitor skeletal muscle changes in dystrophic (mdx4cv) and age-matched control (C57BL/6J) mice starting at 3 weeks of ...age. The objective of this study was to evaluate and characterize changes in muscle tissue characteristics of hind limbs in young, dystrophic mice using MRI. Mdx4cv (n = 25) and age-matched C57BL/6J (n = 5) were imaged at 3, 5, 7, 9, and 11 weeks of age. Multiple MR measurements were taken from the tibialis anterior, gastrocnemius, and soleus muscles. There were significant differences between dystrophic and control groups for all three muscle types when comparing transverse relaxation times (T2) in lower hind limb muscles. Additionally, fractional anisotropy, radial diffusivity, and eigenvalue analysis of diffusion tensor imaging also demonstrated significant differences between groups. Longitudinal relaxation times (T1) displayed no significant differences between groups. The earliest time points in the magnetization transfer ratio measurements displayed a significant difference. Histological analysis revealed significant differences in the tibialis anterior and gastrocnemius muscles between groups with the mdx mice displaying greater variability in muscle fiber size in later time points. The multi-parametric MRI approach offers a promising alternative for future development of a noninvasive avenue for tracking both disease progression and treatment response.
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Dysferlin is a membrane-associated protein implicated in muscular dystrophy and vesicle movement and function in muscles. The precise role of dysferlin has been debated, partly because of the mild ...phenotype in dysferlin-null mice ( Dysf ). We bred Dysf mice to mice lacking myoferlin ( MKO ) to generate mice lacking both myoferlin and dysferlin (FER). FER animals displayed progressive muscle damage with myofiber necrosis, internalized nuclei, and, at older ages, chronic remodeling and increasing creatine kinase levels. These changes were most prominent in proximal limb and trunk muscles and were more severe than in Dysf mice. Consistently, FER animals had reduced ad libitum activity. Ultrastructural studies uncovered progressive dilation of the sarcoplasmic reticulum and ectopic and misaligned transverse tubules in FER skeletal muscle. FER muscle, and Dysf - and MKO -null muscle, exuded lipid, and serum glycerol levels were elevated in FER and Dysf mice. Glycerol injection into muscle is known to induce myopathy, and glycerol exposure promotes detachment of transverse tubules from the sarcoplasmic reticulum. Dysf, MKO , and FER muscles were highly susceptible to glycerol exposure in vitro , demonstrating a dysfunctional sarcotubule system, and in vivo glycerol exposure induced severe muscular dystrophy, especially in FER muscle. Together, these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function and in the genesis of muscular dystrophy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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