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PubMed2026

MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.

BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMD&#x394;52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMD&#x394;52 (DMD) and DMD&#x394;51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks. METHODS: Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5&#x2009;months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC|&#x2009;&#x2265;&#x2009;1, adj. p&#x2009;&#x2264;&#x2009;0.05) and miRNAs (adj. p&#x2009;&#x2264;&#x2009;0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE&#x2009;<&#x2009;-25&#x2009;kcal/mol, seed pairing) filtered by inverse Pearson correlation. RESULTS: Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies. CONCLUSIONS: Exon 51 skipping in the DMD&#x394;52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.

Animals↗
PubMed2005

4,8-Dimethyldecanal, the aggregation pheromone of Tribolium castaneum, is biosynthesized through the fatty acid pathway.

4,8-Dimethyldecanal (4,8-DMD) is the aggregation pheromone produced by male red flour beetles (RFB), Tribolium castaneum. To elucidate the biosynthetic origin of 4,8-DMD, the following studies were performed: (1) effects of juvenile hormone (JH) III, and pathway inhibitors mevastatin, an inhibitor of the mevalonate pathway, and 2-octynoic acid, an inhibitor of the fatty acid pathway, were tested to determine whether 4,8-DMD is derived from the fatty acid pathway or the mevalonate pathway; (2) incorporation of 13C-labeled acetate, propionate, and mevalonolactone into 4,8-DMD was measured to directly determine the biosynthetic origin of 4,8-DMD; and (3) incorporation of deuterium-labeled precursors, including 2-methylbutanoate (C5D), 4-methylhexanoate (C7D), 2,6-dimethyloctanoate (C10D), and 4,8-dimethyldecanoate (C12D) was tested to determine whether 4,8-DMD is biosynthesized in the sequence Ac-Pr-Ac-Pr-Ac (Ac; acetate, Pr; propionate). JH III was topically applied to males at various doses. Inhibitors and isotopically labeled substrates were administered orally by feeding the beetles flour treated with the substrates of interest, after which volatiles were collected from both sexes of RFBs. The amount of 4,8-DMD produced was significantly reduced with increasing doses of JH III. Also, 2-octynoic acid inhibited the production of 4,8-DMD, but mevastatin did not. Exposure of RFBs to [1-(13)C]acetate and [1-(13)C]propionate, but not [2-(13)C]mevalonolactone, resulted in incorporation of the labeled compounds into 4,8-DMD. RFBs fed flour treated with deuterium-labeled C5D, C10D, and C12D, but not C7D, incorporated these compounds into 4,8-DMD. The findings that the production of 4,8-DMD was inhibited by 2-octynoic acid but unaffected by mevastatin, combined with the high incorporation of [1-(13)C]acetate and [1-(13)C]propionate into 4,8-DMD and the incorporation of deuterated precursors, unambiguously demonstrated that 4,8-DMD is of fatty acid rather than terpene biosynthetic origin, and that the biosynthesis of 4,8-DMD proceeds in the sequence Ac-Pr-Ac-Pr-Ac.

Acetates↗
PubMed1987

Membrane fluidity of nonmuscle cells in Duchenne muscular dystrophy: effect on lymphocyte membranes of incubation in patient and control sera.

The membrane fluidity of intact fibroblasts, erythrocyte ghosts, and intact lymphocytes from Duchenne muscular dystrophy (DMD) patients and controls was measured by steady state fluorescence polarization. The fluorescent probes used were diphenylhexatriene (DPH), trimethylammonium-DPH, and a set of n-(9-anthroyloxy) fatty acids. Fluorescence anisotropies in DMD fibroblasts and DMD erythrocyte ghosts were normal. In DMD lymphocytes (n = 10) fluorescence anisotropy of DPH was decreased versus controls (0.212 +/- 0.028 versus 0.231 +/- 0.012, p less than 0.05). Linear regression analysis of creatine kinase activity in sera and DPH fluorescence anisotropy in lymphocytes from DMD patients showed a negative correlation (r = -0.93, p less than 0.001). DMD lymphocytes and control lymphocytes were incubated for 4 h in sera from DMD patients and from controls. When incubated in DMD sera, DPH fluorescence anisotropy of DMD lymphocytes decreased from 0.211 +/- 0.018 to 0.180 +/- 0.028, and fluorescence anisotropy of control lymphocytes decreased from 0.239 +/- 0.012 to 0.179 +/- 0.025 reaching the same level as did DMD lymphocytes. When incubated in control sera, DPH fluorescence anisotropy of DMD lymphocytes increased to 0.224 +/- 0.012, and fluorescence anisotropy of control lymphocytes decreased to 0.218 +/- 0.017. The fluorescence anisotropy changes after incubation in DMD versus control sera were different (p less than 0.05 for DMD lymphocytes and p less than 0.005 for control cells). Our findings do not support the hypothesis of a general membrane defect but suggest a toxic serum factor in DMD which attacks lymphocyte membranes and possibly muscle membranes at the same time.

Adolescent↗
PubMed1982

Erythrocyte-ghost Ca2+-stimulated Mg2+-dependent adenosine triphosphatase in Duchenne muscular dystrophy.

The Ca2+-stimulated Mg2-dependent ATPase activities (Ca2+-ATPase) of erythrocyte-ghost membranes from patients with Duchenne muscular dystrophy (DMD) and carriers of DMD were compared with activities of normal controls. The Ca2+-ATPase activity of DMD-patient ghost preparations was found to follow the same pattern of activation by Ca2+ as the control membranes. However, the Ca2+-ATPase activity in DMD and some DMD-carrier preparations was substantially elevated compared with controls. To characterize further the elevated Ca2+-ATPase activity found in DMD-patient ghost membrane preparations, we estimated kinetic parameters using both fine adjustment and weighting methods to analyse our experimental data. It was established that in both DMD and DMD-carrier preparations the increase in Ca2+-ATPase activity was reflected by a significant increase in Vmax. rather than by any change in Km. The response of the membrane Ca2+-ATPase activity to changes in temperature was also investigated. In all preparations a break in the Arrhenius plot occurred at 20 degrees C, and in DMD and DMD-carrier preparations an elevated Ca2+-ATPase activity was detected at all temperatures. Above 20 degrees C the activation energy for all types of preparation was the same, whereas below this temperature there appeared to be an elevated activation in DMD and DMD-carrier preparations compared with normal controls. The concept that a generalized alteration in the physicochemical nature of the membrane lipid domain may be responsible for the many abnormal membrane properties reported in DMD is discussed.

Adolescent↗
PubMed2005

Body composition and water compartment measurements in boys with Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) patients have a lower percentage of total body water and higher extracellular water to intracellular water (ECW/ICW) ratio compared with normal subjects. However, it is not known whether this is due to increased fat mass or a decreased amount of ICW in muscle cells in DMD patients. The purpose of this study was to (1) determine the effect of increased fat mass and decreased lean mass on the ECW to ICW ratio in DMD patients and to (2) determine the validity of multifrequency bioelectrical impedance analysis (MFBIA) in assessing body composition in DMD patients. DESIGN: This study has a quasi-experimental, comparative design using nonequivalent groups. A total of 46 boys ranging from 6 to 13 yrs of age participated in this study. There were 12 nonobese able-bodied controls, 19 obese able-bodied children (obese), and 15 boys with DMD. Body composition was measured by dual-energy x-ray absorptiometry (DEXA). Body composition and body water compartment analysis were assessed by MFBIA. All measurements obtained using MFBIA were compared with those obtained using DEXA for validation. RESULTS: Both MFBIA and DEXA measures were strongly correlated in control (r = 0.99), obese (r = 0.92), and DMD subjects (r = 0.95). However, lean tissue mass measured by DEXA in the DMD subjects was only slightly higher (19.2 +/- 1.1 vs. 18.2 +/- 1.2, P < 0.02) than as measured by MFBIA. Mean percentage of body fat measured by DEXA in the DMD subjects (30.4 +/- 3.1%) was significantly lower than as measured by MFBIA (38.7 +/- 2.2%). The mean percentage of body fat measured by DEXA in the control group (23.2 +/- 1.8%) was significantly (P < 0.001) lower than as measured by MFBIA (28.6 +/- 1.6%). The mean percentage of body fat measured by DEXA in obese able-bodied controls (40.8 +/- 0.9%) was not significantly different from that measured by MFBIA (40.4 +/- 1.5%). Compared with the obese and control subjects, DMD subjects showed reduced ICW and ECW, with an increased ECW/ICW ratio, as expected. However, the percentage of fat for the DMD group was not different from the obese group. CONCLUSIONS: DMD patients have elevated ECW/ICW ratios compared with obese subjects and nonobese controls. However, obese subjects and nonobese controls had similar ECW/ICW ratios, despite the increased fat tissue mass in obese subjects. This suggests that the elevated ECW/ICW ratios in DMD subjects are not due to increased fat mass but rather some other mechanism, likely impaired cellular homeostasis due to muscle membrane instability. Although MFBIA slightly underestimates lean tissue mass in boys with DMD, it has a potential role as an inexpensive and easy to use measurement tool to measure changes in muscle mass in the clinical setting.

Absorptiometry, Photon↗
PubMed1985

Dissociation of insulin resistance and decreased insulin receptor binding in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disease characterized by progressive weakness and severe muscle wasting. Alterations in carbohydrate metabolism are often associated with neuromuscular disorders. We performed oral glucose tolerance tests and insulin binding studies on erythrocytes from 17 DMD and 8 normal males. Furthermore, we measured insulin binding to erythrocytes from 12 normal males and from 11 mothers and 10 sisters of affected males. As a group, DMD patients had mild glucose intolerance and both fasting and postabsorptive marked hyperinsulinemia (insulin resistance). Levels of glucose and insulin, expressed as incremental areas under their respective curves, were significantly elevated in the wheelchair-ridden patients. Incremental areas of glucose (0-2 h) and insulin (0-5 h) were 42 +/- 5 mg/dl X h (mean +/- SEM) and 96 +/- 18 microU/ml X h, respectively, in normal subjects and 71 +/- 6 (P less than 0.05) and 206 +/- 30 (P less than 0.05), respectively, in the wheelchair-confined DMD patients. All of the ambulatory DMD males had normal oral glucose tolerance tests. Insulin binding to erythrocytes was 20-30% lower (P less than 0.01) in all DMD patients than in normal males appropriately matched for age and degree of sexual development. This difference in binding was a result of lower affinity of the insulin receptor in DMD erythrocytes. On the other hand, insulin binding to fibroblasts was the same in normal males and DMD patients, suggesting that the abnormality of erythrocyte binding in DMD is probably not genetically induced. Insulin binding to erythrocytes and monocytes was the same in all females studied, regardless of whether they were carriers of the DMD gene. Our results suggest that abnormal insulin binding in DMD erythrocytes is an acquired rather than genetic abnormality, but insulin binding is not helpful in the identification of carrier females. The defect in insulin binding in DMD is present before the development of insulin resistance, which occurs only in severely immobilized patients. Thus, the cause of the insulin resistance in DMD may reside at steps beyond the binding of insulin to its receptor.

Adult↗
PubMed2006

Visual recovery after scleral buckling surgery in macula-off rhegmatogenous retinal detachment.

PURPOSE: The primary goal of this study was to investigate the functional results after scleral buckling (SB) surgery in macula-off rhegmatogenous retinal detachment (RRD), with more or less than 7 days' duration of macular detachment (DMD). The secondary outcome measure was to determine the long-term functional results in these two groups 5 years after SB surgery. METHODS: The retrospective studies included 96 eyes of 96 patients with primary, uncomplicated, macula-off RRD. Two studies, one with a short-term follow-up and one with a long-term follow-up, were performed, and in both studies the eyes were divided into two groups according to the DMD. In study I, 96 patients were divided into DMD or=4 days and 7 days (n = 11). Additional preoperative predictive factors including DMD, preoperative visual acuity (VA) and patients' age at the time of the RRD were correlated with the postoperative VA. RESULTS: In study I, the mean final VA was significantly better (0.45) after a DMD of less than or equal to 7 days, compared to patients with a DMD of more than 7 days (0.22; Student's t test, p = 0.02). VA >or=0.4 was achieved in 68% with a subacute DMD compared to 52% in patients with prolonged DMD (chi(2) test, p < 0.001). However, the postoperative VA (0.48 +/- 0.09) in eyes with DMD of 1-3 days was similar (0.42 +/- 0.07) to eyes with DMD of 4-7 days (Student's t test, p = 0.455). We divided the 96 patients into 2 groups according to a preoperative VA. Eyes with a preoperative VA 0.1 (n = 34; Student's t test, p < 0.001). Patients 75 years of age or younger were more likely to achieve a VA of 0.4 or better after SB surgery than older patients (more than 75 years; chi(2) test, p = 0.008). In study II, VA improved (by a mean of 1.60 +/- 0.02 lines) during the follow-up period from 0.32 +/- 0.08 at the 3-month follow-up to 0.46 +/- 0.10 at the 5-year follow-up. Eyes with a subacute DMD had a significantly better VA than eyes with a prolonged DMD (Student's t test, p = 0.004). Patients aged 75 years or less were more likely to achieve a VA of 0.4 or better than patients older than 75 (chi(2) test, p = 0.003). CONCLUSION: The time point of SB surgery has no statistical impact on the final visual recovery in patients with an acute primary macular-off RRD of less than or equal to 7 days. A delay of SB surgery within this time frame does not contribute to an impaired final visual outcome. There was no evidence, that primary macula-off RRDs are emergencies, which cannot wait for a systemic evaluation of the RRD and surgical treatment at the next available scheduled day. A preoperative VA of more than 0.1 and patients' age under 60 years at presentation had an additional prognostic value on the final outcome. Surgeons should be aware that visual function after reattachment may continue to improve over a long period. This study provides useful guidelines for the clinical management of macula-off RRD and the assessment of potential visual recovery in patients after successful SB surgery.

Adolescent↗
PubMed2005

Biochemical markers of bone metabolism and risk of dorsal metacarpal disease in 2-year-old Thoroughbreds.

REASONS FOR PERFORMING STUDY: Dorsal metacarpal disease (DMD) is a common problem in 2-year-old racehorses and results in loss of a significant number of days from training. Biochemical markers of bone cell activity measured early in the training season could have value for identifying 2-year-old Thoroughbred racehorses that develop DMD. OBJECTIVES: To determine the association between serum concentrations of osteocalcin, the carboxyterminal propeptide of type I collagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) measured early in the training season and the risk of DMD. METHODS: Blood samples were collected from 165 two-year-old Thoroughbreds during late November/early December. Osteocalcin and PICP were measured as markers of bone formation, and ICTP as a marker of bone resorption. Training and veterinary records for each horse were monitored over the following training/racing season (10 months). Cases were defined as an episode where signs of DMD were sufficiently severe for a horse to miss at least 5 consecutive days of training. Classification tree and logistic regression analysis were used to identify the most important factors suitable for prediction of DMD risk. RESULTS: There were 24 cases of DMD during the season (14.6% cumulative incidence), with an average time to recognition of approximately 6 months (May). The earliest recognised case was in February and the latest in September. Osteocalcin and ICTP concentrations in the early stages of the training season were significantly higher in horses that subsequently developed DMD (P = 0.017 and 0.019, respectively). DMD cases were also significantly older compared to noncases (21.04 vs. 20.44 months, P = 0.023). Using a multivariable logistic regression model, it was possible to postulate a set of diagnostic rules to predict the likelihood of DMD injury during the season. This suggested that horses with ICTP concentrations above 12365 ug/l and older than 20.5 months are 2.6 times more likely to develop DMD. CONCLUSIONS: The measurement of the bone resorption marker ICTP could be useful for identification of 2-year-olds at increased risk of developing DMD. POTENTIAL RELEVANCE: These findings, together with other strategies such as modification of training regimens, e.g. early introduction of short distances of high-speed exercise into the training programme, could help reduce the days lost to training as a result of DMD.

Age Factors↗
PubMed2005

A new model mouse for Duchenne muscular dystrophy produced by 2.4 Mb deletion of dystrophin gene using Cre-loxP recombination system.

Duchenne muscular dystrophy (DMD) is caused by mutation in the 2.4-Mb dystrophin (DMD) gene . This gene encodes a number of tissue-specific isoforms of dystrophin generated by transcription from at least seven promoters and also by alternative splicing. We deleted entire genomic region of the DMD gene on mouse chromosome X using a Cre-loxP recombination system. Introduction of a loxP site in dystrophin's first and last exon by homologous recombination in mouse embryonic stem (ES) cells generated "DMD-floxed" (flanked by loxP sites) ES cells, which we subjected to Cre-mediated excision leading to establishment of "DMD-null" ES cell lines. The DMD-null mice produced from the DMD-null ES cells were viable but displayed severe muscular hypertrophy and dystrophy. In addition to the muscular impairment, the DMD-null mouse exhibited some behavioral abnormality and male sterility. The DMD-floxed mice produced from the DMD-floxed ES cells were viable, phenotypically normal, and were born with the expected Mendelian frequency, despite the absence of brain (cortical)-type dystrophin (Dp427c) expression. Since production of multiple dystrophin isoforms due to alternative splicing or exon skipping is totally prevented in the DMD-null mouse, these new mutants will provide an improved model system for functional studies of dystrophin and its isoforms.

Animals↗
PubMed2005

Evolution of gastric electrical features and gastric emptying in children with Duchenne and Becker muscular dystrophy.

OBJECTIVES: Although muscular dystrophy (MD) affects primarily striated muscles, smooth muscle cells of the gastrointestinal tract may also be involved. We recorded gastric electrical activity and gastric emptying time (GET) in children with MD at initial presentation and at 3-yr follow-up in order to detect gastric motor abnormalities and study their evolution along the clinical course. METHODS: Twenty children with MD (median age: 4.6 yr; range age: 3-7 yr) were investigated by means of ultrasonography, for measuring GET, and by electrogastrography (EGG); 70 children served as controls. RESULTS: Ten patients had Duchenne muscular dystrophy (DMD) and 10 Becker muscular dystrophy (BMD). GET was significantly more delayed in MD patients (DMD, median: 195 min; range 150-260 min; BMD, median: 197 min; range: 150-250 min) than in controls (median: 150 min; 110-180 min; p < 0.05); it markedly worsened at the follow-up in DMD (median: 270 min; range 170-310 min; p < 0.001 vs controls) but not in BMD patients (median: 205 min; 155-275 min; p < 0.05 vs DMD). Baseline EGG showed a significantly lower prevalence of normal rhythm and significantly higher prevalence of dysrhythmias in both groups of patients as compared to controls (% of normal rhythm: DMD 66.7 +/- 8.2, BMB 67.2 +/- 11.5, controls 85.3 +/- 7.2, p < 0.001; % of tachygastria: DMD 28.4 +/- 8.0, BMB 29.8 +/- 12.3, controls 10.6 +/- 5.1, p < 0.001; % of dominant frequency instability coefficient: DMD 36.1 +/- 6.0, BMB 33.2 +/- 2.9, controls 17.9 +/- 7.1, p < 0.001); furthermore, no difference in fed-to-fasting ratio of the dominant EGG power was found between the two groups and controls (DMD 2.84 +/- 1.27, BMB 2.82 +/- 0.98, controls 3.04 +/- 0.85, ns). However, at the follow-up no significant change in the prevalence of normal rhythm and dysrhythmias occurred in both groups (ns vs baseline values), whereas only DMD patients showed a marked reduction in fed-to-fasting power ratio (0.78 +/- 0.59; p < 0.001 vs controls and BMD; p < 0.05 vs baseline), which correlated with the progressive neuromuscular weakness occurring in DMD subjects (r, 0.75; p < 0.001). CONCLUSIONS: In children with MD, there is an early abnormality in gastric motility that is due to deranged regulatory mechanisms, whereas contractile activity of smooth muscle cells seems to be preserved. At the follow-up, DMD patients exhibited a progressive failure in neuromuscular function, which was accompanied by a gastric motility derangement with worsening in GET and in EGG features suggesting an altered function of gastric smooth muscle cells.

Child↗