Serum levels of vascular endothelial growth factor elevated in patients with muscular dystrophy

In patients with muscular dystrophy, such as Duchenne muscular dystrophy (DMD), microcirculation abnormalities and hypoxic ischemic conditions in muscle tissues are suspected to be induced by non-symptomatic coagulation fibrinolysis abnormalities and vascular dysfunction. Vascular endothelial growth factor (VEGF) is a critical regulating factor in angiogenesis that is known to be induced by hypoxic and/or ischemic conditions. To examine whether VEGF is associated with muscular dystrophy, we measured serum levels of VEGF in 52 patients with DMD, 15 with Becker muscular dystrophy (BMD), 20 with Fukuyama congenital muscular dystrophy (FCMD), eight with myotonic dystrophy (DM), and four with spinal muscular atrophy (SMA), as well as in 15 healthy and eight disease controls. The serum level of VEGF in the DMD patients was 267.7 ± 25.3 pg/ml (10.5–800.0), while it was 358.8 ± 96.3 pg/ml (0.2–1320.0) in the BMD patients, 261.4 ± 45.6 pg/ml (0.1–758.0) in the FCMD patients, 165.0 ± 63.4 pg/ml (2.6–479.0) in the DM patients, 96.0 ± 30.3 pg/ml (41.0–168.0) in the SMA patients, 148.3 ± 20.1 pg/ml (46.5–298.0) in the healthy controls, and 154.1 ± 54.0 pg/ml (7.2–343.0) in the disease controls. The level of VEGF in BMD was significantly elevated, as compared with DM, SMA, and control groups. Further, the level of VEGF in the bedridden sub-group of DMD patients was significantly elevated as compared with chair-bound DMD, DM, SMA, and control groups. We concluded that VEGF may reflect hypoxic and/or ischemic conditions in muscle tissue, and have a relationship with the process of disease progression in DMD and BMD patients.     

Exercise and Duchenne muscular dystrophy: where we have been and where we need to go

Introduction: In this study we investigated whether an association exists between muscle fiber conduction velocity (MFCV) and local muscle oxygen saturation (StO ₂) in the superficial part of the latissimus dorsi muscle of runners and swimmers during exhaustive dynamic exercise. Methods: Participants performed arm cranking with increasing intensity until exhaustion. Results: Runners' MFCV was unchanged with increasing arm‐cranking exercise intensity, but was higher (P < 0.05) than swimmers' MFCV at the same workload. Swimmers' MFCV increased (P < 0.05) with increasing exercise intensity and reached values at exhaustion similar to those of the runners. StO ₂ was similar in swimmers and runners at rest and decreased with increasing exercise intensity. StO ₂ was higher (P < 0.05) at the same workload in swimmers compared with runners. StO ₂ and MFCV were significantly but very weakly correlated in both swimmers and runners. Conclusion: No association exists between surface MFCV and StO ₂ in either trained or untrained human skeletal muscle during exhaustive intense dynamic exercise. Muscle Nerve, 2012     

Comparison of X‐chromosome inactivation in Duchenne muscle/myocardium‐manifesting carriers,non‐manifesting carriers and related daughters

Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5–7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X‐chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non‐manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation‐based assay. The results showed that DMD‐manifesting carriers had a preferential inactivation of the X‐chromosome carrying the normal allele, while non‐manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother–daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non‐random patterns of X inactivation.     

High resolution NMR based analysis of serum lipids in Duchenne muscular dystrophy patients and its possible diagnostic significance

Proton NMR spectroscopic investigations on the lipid extract of the serum of 41 Duchenne muscular dystrophy (DMD) (age, mean ± SD; 8.0 ± 3.0 years) patients and 22 healthy subjects (age, mean ± SD; 9.0 ± 4.0 years) were performed in the northern Indian population. The concentration of triglycerides, phospholipids, free cholesterol, cholesterol esters and total cholesterol was significantly higher in DMD patients as compared to healthy subjects. Ratio of free‐cholesterol to cholesterol‐esters was also significantly higher in DMD patients. Among the individual lipids, concentration of phospholipids was found to be consistently higher in DMD patients compared to healthy subjects, with a discriminatory index of 87.5%. The highest discriminatory index of 92% was found along with the ratio of PL (phospholipids) to CHOL (cholesterol), i.e. PL/CHOL. No significant quantitative difference was observed in the serum lipid constituents of positive and negative gene deletion cases of DMD. The inferences drawn from this study may provide the possibility of the diagnostic importance for DMD, especially in cases where genetic analysis fails to provide the diagnosis. Copyright © 2009 John Wiley & Sons, Ltd.     

Understanding the beneficial effects of doxycycline on the dystrophic phenotype of the mdx mouse

Introduction: The purpose of this study was to better understand the beneficial effects of doxycycline on the dystrophic muscles of the mdx mouse. Methods: Doxycycline (DOX) was administered for 36 days, starting on postnatal day 0, via drinking water. Untreated mdx mice received plain water for the same period and served as a control group. Results: DOX decreased the levels of metalloproteinase‐9 and tumor necrosis factor‐alpha in the biceps brachii and diaphragm of the mdx mice. It also reduced the total amount of calcium in the muscles studied, concomitant with an increase in the levels of calsequestrin 1. Conclusions: The results show that DOX can affect factors that are important in dystrophic pathogenesis and highlight its potential as a readily accessible therapy in clinical trials for treatment of Duchenne muscular dystrophy. Muscle Nerve 50:283–286, 2014     

Family‐based genome‐wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate

The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X‐linked syndromes [midline 1 (MID1), oral‐facial‐digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X‐linked genes in the etiology of isolated CL±P in a South American population through a family‐based genome‐wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11‐kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P‐associated X‐chromosome genomic segments.     

Age‐dependent changes in metabolite profile and lipid saturation in dystrophic mice

Duchenne Muscular Dystrophy (DMD) is a fatal X‐linked genetic disorder. In DMD, the absence of the dystrophin protein causes decreased sarcolemmal integrity resulting in progressive replacement of muscle with fibrofatty tissue. The effects of lacking dystrophin on muscle and systemic metabolism are still unclear. Therefore, to determine the impact of the absence of dystrophin on metabolism, we investigated the metabolic and lipid profile at two different, well‐defined stages of muscle damage and stabilization in mdx mice. We measured NMR‐detectable metabolite and lipid profiles in the serum and muscles of mdx mice at 6 and 24 weeks of age. Metabolites were determined in muscle in vivo using ¹H MRI/MRS, in isolated muscles using ¹H‐HR‐MAS NMR, and in serum using high resolution ¹H/¹³C NMR. Dystrophic mice were found to have a unique lipid saturation profile compared with control mice, revealing an age‐related metabolic change. In the 6‐week‐old mdx mice, serum lipids were increased and the degree of lipid saturation changed between 6 and 24 weeks. The serum taurine‐creatine ratio increased over the life span of mdx, but not in control mice. Furthermore, the saturation index of lipids increased in the serum but decreased in the tissue over time. Finally, we demonstrated associations between MRI‐T₂, a strong indicator of inflammation/edema, with tissue and serum lipid profiles. These results indicate the complex temporal changes of metabolites in the tissue and serum during repetitive bouts of muscle damage and regeneration that occur in dystrophic muscle.     

Elevated Cardiac Troponin T in Patients With Skeletal Myopathies

Background

Cardiac troponins are often elevated in patients with skeletal muscle disease who have no evidence of cardiac disease.