Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these de-vastating diseases.
Codon, Nonsense ; Dystrophin ; Genetic Therapy ; Models, Animal ; Models, Theoretical ; Muscles ; Muscular Dystrophies ; Muscular Dystrophy, Duchenne ; Oligonucleotides, Antisense ; Proteins ; RNA

Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno-associated viral vector (AAV). Overexpression of wild-type FST in normal mice greatly increased muscle mass while decreasing fat accumulation, whereas overexpression of an N terminus mutant or N terminus-deleted FST had no effect on muscle mass but moderately decreased fat mass. In contrast, FST-I-I containing the complete N terminus and double domain I without domain II and III had no effect on fat but increased skeletal muscle mass. The effects of different constructs on differentiated C2C12 myotubes were consistent with the in vivo finding. We hypothesized that ND was critical for myostatin blockade, mediating the increase in muscle mass, and was less pivotal for activin binding, which accounts for the decrease in the fat tissue. An in vitro TGF-beta1-responsive reporter assay revealed that FST-I-I and N terminus-mutated or -deleted FST showed differential responses to blockade of activin and myostatin. Our study provided direct in vivo evidence for a role of the ND of FST, shedding light on future potential molecular designs for FST-based gene therapy.
Activins ; Animals ; Follistatin* ; Genetic Therapy ; In Vitro Techniques ; Mice ; Muscle Fibers, Skeletal ; Muscle, Skeletal ; Muscular Dystrophies ; Myostatin ; Negotiating

OBJECTIVETo review the recent research progress in dystrophin-related muscular dystrophy includes X-linked hereditary Duchenne and Becker muscular dystrophies (DMD and BMD).

DATA SOURCESInformation included in this article was identified by searches of PUBMED and other online resources using the key terms DMD, dystrophin, mutations, animal models, pathophysiology, gene expression, stem cells, gene therapy, cell therapy, and pharmacological. Study selection Mainly original milestone articles and timely reviews written by major pioneer investigators of the field were selected.

RESULTSThe key issues related to the genetic basis and pathophysiological factors of the diseases were critically addressed. The availabilities and advantages of various animal models for the diseases were described. Major molecular and cellular therapeutic approaches were also discussed, many of which have indeed exhibited some success in pre-clinical studies but at the same time encountered a number of technical hurdles, including the efficient and systemic delivery of a functional gene and myogenic precursor/stem cells to repair genetic defects.

CONCLUSIONSFurther understanding of pathophysiological mechanisms at molecular levels and regenerative properties of myogenic precursor/stem cells will promote the development of multiple therapeutic strategies. The combined use of multiple strategies may represent the major challenge as well as the greatest hope for the therapy of these diseases in coming years.

Animals ; Disease Models, Animal ; Dystrophin ; genetics ; physiology ; Genetic Therapy ; methods ; Humans ; Models, Biological ; Muscular Dystrophies ; genetics ; physiopathology ; therapy ; Mutation ; genetics ; Utrophin ; therapeutic use

The purpose of this study was to analyze the STR loci expression after allergenic cord hematopoietic stem cell transplantation in patient with Ducennes muscular dystropy (DMD) patient. PCR-SSO was used to identify the HLA antigens and alleles, STR-PCR was used to detect the chimera status. Quantity analysis of donor chimeras was performed by multiplex PCR amplification of STR marker and capillary electrophoresis with fluorescence detection. The results showed that patient appear to be HLA identical to the donor cord blood at the tested level. Persistent full donor chimerism was found in breast bone marrow. The patient with stable MC (DC < 5%) had a probability of long term survival with molecular remission MC status appeared in forearm muscle, tongue, liver, spleen, stomach, right temporal lobe, diaphragmatic muscle, bronchus, left ventricle and right kidney. In conclusion, the donor gene can express in parenchymatoas organs, the donor chimerism was detected in breast bone marrow and some other organs.
Child ; Cord Blood Stem Cell Transplantation ; Genetic Loci ; genetics ; Humans ; Male ; Microsatellite Repeats ; genetics ; Muscular Dystrophies ; genetics ; therapy ; Transplantation Chimera ; Transplantation, Homologous

OBJECTIVE: Cell therapy has been extensively studied as a gene complementation approach in muscular dystrophy including Duchenne muscular dystrophy (DMD), and adipose tissue has recently been identified as a uniquely abundant and adequately accessible source of pluripotent cells. In the present work, we investigated myogenic potentials of adipose-derived stem cells (ADSCs) depending on culture media and isolation with using surface markers. METHOD: Human ADSCs were obtained by liposuction and cultured in two different media; control and myogenic media. In addition we attempted to isolate ADSCs by utilizing surface markers: CD45 and CD133. The following observations were made to evaluate myogenic differentiation as the expression of myogenic regulatory factors (MyoD, Myf-5 and Myf-6) and desmin by RT-PCR and immunoflurescence study. RESULTS: Conversion of ADSCs to myogenic phenotype was observed by indirect immunoflurescence study of MyoD and Myf-5 in regardless of media type and isolation method. In addition mRNA of MyoD and Myf-5 were positive in both culture media, and there were no differences of MyoD and Myf-5 responses between CD45- and CD45-CD133-ADSCs. However, secondary myogenic regulatory factor (Myf-6) was not expressed constantly, and desmin were negative in all cultural condition. CONCLUSION: Our findings suggest that human ADSCs might have myogenic potentials. However, further studies are needed to express the secondary myogenic regulatory factors and proteins in myoblasts.
Adipose Tissue ; Complement System Proteins ; Culture Media ; Desmin ; Genes, vif ; Humans ; Lipectomy ; Muscular Dystrophies ; Muscular Dystrophy, Duchenne ; Myoblasts ; Myogenic Regulatory Factors ; Phenotype ; Proteins ; RNA, Messenger ; Stem Cells ; Tissue Therapy

BACKGROUNDLate-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common type of lipid storage myopathies in China. Most patients with late-onset MADD are well responsive to riboflavin. Up to now, these patients are often treated with glucocorticoids as the first-line drug because they are misdiagnosed as polymyositis without muscle biopsy or gene analysis. Although glucocorticoids seem to improve the fatty acid metabolism of late-onset MADD, the objective evaluation of their rationalization on this disorder and comparison with riboflavin treatment are unknown.

METHODSWe performed a historical cohort study on the efficacy of the two drugs among 45 patients with late-onset MADD, who were divided into glucocorticoids group and riboflavin group. Detailed clinical information of baseline and 1-month follow-up were collected.

RESULTSAfter 1-month treatment, a dramatic improvement of muscle strength was found in riboflavin group (P < 0.05). There was no significant difference in muscle enzymes between the two groups. Significantly, the number of patients with full recovery in glucocorticoids group was less than the number in riboflavin group (P < 0.05). On the other hand, almost half of the patients in riboflavin group still presented high-level muscle enzymes and weak muscle strength after 1-month riboflavin treatment, meaning that 1-month treatment duration maybe insufficient and patients should keep on riboflavin supplement for a longer time.

CONCLUSIONSOur results provide credible evidences that the overall efficacy of riboflavin is superior to glucocorticoids, and a longer duration of riboflavin treatment is necessary for patients with late-onset MADD.

Adolescent ; Adult ; Age of Onset ; Child ; Cohort Studies ; Female ; Glucocorticoids ; therapeutic use ; Humans ; Lipid Metabolism, Inborn Errors ; therapy ; Male ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; drug therapy ; Muscular Dystrophies ; therapy ; Riboflavin ; therapeutic use ; Young Adult

PURPOSE: To survey the use of invasive and noninvasive home mechanical ventilation (HMV) methods in South Korea from the perspective of physical medicine and rehabilitation (PM&R). MATERIALS AND METHODS: For 413 users of HMV, retrospective reviews of PM&R interventions and survey of HMV methods employed from Mar 2000 to Dec 2009. RESULTS: Of the 413 users, the majority of whom with progressive neuromuscular disorders (NMDs) (n=358), 284 patients initially used noninvasive mechanical ventilation (NIV), while 63 others who were using tracheostomy mechanical ventilation switched to NIV as part of their rehabilitation. The NMD patients began HMV at an earlier age (34.9+/-20.3 yrs), and used for longer (14.7+/-7.5) hours than patients with non-neuromuscular causes of respiratory impairment. CONCLUSION: Noninvasive management was preferred over invasive ones, and transition to the former was a result of PM&R interventions.
Adult ; Female ; Health Care Surveys ; Home Care Services/*statistics & numerical data ; Humans ; Male ; Middle Aged ; Muscular Dystrophies/*therapy ; Neuromuscular Diseases/therapy ; Republic of Korea ; Respiration, Artificial/*statistics & numerical data ; Retrospective Studies ; Ventilators, Mechanical/*statistics & numerical data

PURPOSE: This study aimed to evaluate the clinical findings in pediatric rhabdomyolysis and the predictive factors for acute kidney injury (AKI) in Korean children. METHODS: Medical records of 39 Korean children, who were newly diagnosed with rhabdomyolysis from January 2008 to December 2015, were retrospectively analyzed. The diagnosis was made from the medical history, elevated serum creatinine kinase level >1,000 IU/L, and plasma myoglobin level >150 ng/mL. Patients with muscular dystrophy and myocardial infarction were excluded. RESULTS: The median patient age at diagnosis was 14.0 years (range, 3–18 years), and the male to female ratio was 2.5. The most common presenting symptom was myalgia (n=25, 64.1%), and 14 patients (35.9%) had rhabdomyolysis-induced AKI. Eighteen patients (46.2%) had underlying diseases, such as epilepsy and psychotic disorders. Ten of these patients showed rhabdomyolysis-induced AKI. The common causes of rhabdomyolysis were infection (n=12, 30.7%), exercise (n=9, 23.1%), and trauma (n=8, 20.5%). There was no difference in the distribution of etiology between AKI and non-AKI groups. Five patients in the AKI group showed complete recovery of renal function after stopping renal replacement therapy. The median length of hospitalization was 7.0 days, and no mortality was reported. Compared with the non-AKI group, the AKI group showed higher levels of peak creatinine kinase and myoglobin, without statistical significance. CONCLUSION: The clinical characteristics of pediatric rhabdomyolysis differ from those observed in adult patients. Children with underlying diseases are more vulnerable to rhabdomyolysis-induced AKI. AKI more likely develops in the presence of a high degree of albuminuria.
Acute Kidney Injury* ; Adult ; Albuminuria ; Child ; Creatinine ; Diagnosis ; Epilepsy ; Female ; Hospitalization ; Humans ; Male ; Medical Records ; Mortality ; Muscular Dystrophies ; Myalgia ; Myocardial Infarction ; Myoglobin ; Phosphotransferases ; Plasma ; Psychotic Disorders ; Renal Replacement Therapy ; Retrospective Studies ; Rhabdomyolysis*