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Annals of Neurology Nov 2013In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).
METHODS
DMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n = 4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT.
RESULTS
At week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p≤0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p≤0.001).
INTERPRETATION
Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.
Topics: Adolescent; Child; Double-Blind Method; Dystrophin; Humans; Male; Morpholinos; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Mutation; Oligonucleotides; Treatment Outcome
PubMed: 23907995
DOI: 10.1002/ana.23982 -
Frontiers in Bioscience (Landmark... Jan 2016In skeletal muscle, the dystrophin-associated glycoprotein complex forms a link between the actin cytoskeleton and the extracellular matrix that is critical for muscle... (Review)
Review
In skeletal muscle, the dystrophin-associated glycoprotein complex forms a link between the actin cytoskeleton and the extracellular matrix that is critical for muscle integrity. Within this complex resides the sarcoglycan subcomplex, which consists of four transmembrane glycoproteins (alpha-, beta-, gamma-, and delta-sarcoglycan). During assembly, beta-sarcoglycan tightly associates with delta-sarcoglycan to form a functional core that then recruits gamma- and alpha-sarcoglycan to form the sarcoglycan complex. Together with sarcospan, the sarcoglycan complex binds other components of the dystrophin-associated glycoprotein complex and integrates into the myofibre's membrane. Once integrated, the sarcoglycan complex plays a pivotal role in mechanically stabilising the sarcolemma as well as the dystrophin-associated glycoprotein complex. Additionally, the sarcoglycan complex undergoes chemical modifications in response to muscle contractions, thereby transducing mechanical information into a cellular signal. Mutations in the sarcoglycans induce limb girdle muscular dystrophy, and several animal models have been established to study the molecular biology and function of the sarcoglycan complex. This review discusses the role of the sarcoglycan complex in skeletal muscle and describes the functional deficiencies that lead to muscular dystrophies.
Topics: Humans; Muscle, Skeletal; Phylogeny; Sarcoglycans
PubMed: 26709803
DOI: 10.2741/4418 -
Current Opinion in Pharmacology May 2024Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding... (Review)
Review
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
PubMed: 38713975
DOI: 10.1016/j.coph.2024.102459 -
Italian Journal of Pediatrics Nov 2016Vescico-Ureteral Reflux (VUR) is a common condition in childhood, caused by a congenital anomaly at the Vescico-Ureteral Junction (VUJ) level. It seems that the main... (Review)
Review
Vescico-Ureteral Reflux (VUR) is a common condition in childhood, caused by a congenital anomaly at the Vescico-Ureteral Junction (VUJ) level. It seems that the main cause could be an abnormal embryological development occurred during the early stage of fetal life.Refluxing ureteral endings show structural and functional anomalies: previous studies have shown a significant decrease in alfa actin, miosin and desmin contents as well as an high rate of atrophy and muscular degeneration with disorganized muscular fibres. The roles played by Cajal cells and Connexin 43 in generating peristaltic waves appears to be fundamental for the physiological VUJ function and activity. Attention was focused also on the congenital muscular deficiency of the RUs, on regard to general morphology, smooth muscle cells architecture, inflammatory markers and the distribution of collagen composition.This review will discuss and investigate the importance of the modified configuration of Sarcoglycan (SG) sub complex (particularly the deficiency of the ε-SG and the increased expression of the α-SG), the role played by Cajal Cells, the intravescical tunnel length to ureteral diameter ratio as possible causes of the functional alterations in the refluxing ureteral ends leading towards the VUJ incompetence.
Topics: Humans; Infant, Newborn; Risk Factors; Sarcoglycans; Vesico-Ureteral Reflux
PubMed: 27899160
DOI: 10.1186/s13052-016-0316-x -
Frontiers in Cell and Developmental... 2022Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its...
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-COs lack initial proliferative capacity, displayed a progressive loss of sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, cardiomyocyte deterioration, fibrosis and aberrant adipogenesis were observed in DMD-COs over time. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-COs which was associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable 3D human cardiac-mimics to study DMD-related cardiomyopathies.
PubMed: 36035984
DOI: 10.3389/fcell.2022.878311 -
Neuromuscular Disorders : NMD Dec 2012Fatigue is a frequent complaint in muscular dystrophies but it is yet not well defined or studied. We have examined the issue of muscle fatigue in a series of... (Review)
Review
Fatigue is a frequent complaint in muscular dystrophies but it is yet not well defined or studied. We have examined the issue of muscle fatigue in a series of molecularly defined muscular dystrophies. A greater fatigability is seen in muscular dystrophy patients and can be an acute or chronic status. In Duchenne Muscular Dystrophy and beta-sarcoglycanopathy besides the alteration of dystrophin and/or sarcoglycan complex, a neuronal nitric oxide synthase depletion is frequently found and might correlate with post-exercise fatigability as well as with cardiac involvement. Therefore, it might be an important modulating factor of the severity of myopathy. In myotonic dystrophy, fatigue is a common complaint: muscle is involved and type 1 atrophy is a frequent feature; brain involvement and depressed mood might likely explain the extent of fatigue and daytime sleepiness commonly observed in these patients. Furthermore, in our observation in a series of 24 cases, muscle and brain can be independently involved in DM1 patients. These observations have profound impact on the type of physical therapy to be prescribed in such patients.
Topics: Exercise; Humans; Muscle Fatigue; Muscular Diseases; Muscular Dystrophy, Duchenne; Nitric Oxide Synthase Type I
PubMed: 23182642
DOI: 10.1016/j.nmd.2012.10.010 -
Skeletal Muscle Jan 2022The sarcoglycan complex (SC) is part of a network that links the striated muscle cytoskeleton to the basal lamina across the sarcolemma. The SC coordinates changes in...
BACKGROUND
The sarcoglycan complex (SC) is part of a network that links the striated muscle cytoskeleton to the basal lamina across the sarcolemma. The SC coordinates changes in phosphorylation and Ca-flux during mechanical deformation, and these processes are disrupted with loss-of-function mutations in gamma-sarcoglycan (Sgcg) that cause Limb girdle muscular dystrophy 2C/R5.
METHODS
To gain insight into how the SC mediates mechano-signaling in muscle, we utilized LC-MS/MS proteomics of SC-associated proteins in immunoprecipitates from enriched sarcolemmal fractions. Criteria for inclusion were co-immunoprecipitation with anti-Sgcg from C57BL/6 control muscle and under-representation in parallel experiments with Sgcg-null muscle and with non-specific IgG. Validation of interaction was performed in co-expression experiments in human RH30 rhabdomyosarcoma cells.
RESULTS
We identified 19 candidates as direct or indirect interactors for Sgcg, including the other 3 SC proteins. Novel potential interactors included protein-phosphatase-1-catalytic-subunit-beta (Ppp1cb, PP1b) and Na-K-Cl-co-transporter NKCC1 (SLC12A2). NKCC1 co-localized with Sgcg after co-expression in human RH30 rhabdomyosarcoma cells, and its cytosolic domains depleted Sgcg from cell lysates upon immunoprecipitation and co-localized with Sgcg after detergent permeabilization. NKCC1 localized in proximity to the dystrophin complex at costameres in vivo. Bumetanide inhibition of NKCC1 cotransporter activity in isolated muscles reduced SC-dependent, strain-induced increases in phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). In silico analysis suggests that candidate SC interactors may cross-talk with survival signaling pathways, including p53, estrogen receptor, and TRIM25.
CONCLUSIONS
Results support that NKCC1 is a new SC-associated signaling protein. Moreover, the identities of other candidate SC interactors suggest ways by which the SC and NKCC1, along with other Sgcg interactors such as the membrane-cytoskeleton linker archvillin, may regulate kinase- and Ca-mediated survival signaling in skeletal muscle.
Topics: Animals; Chromatography, Liquid; Humans; Mice; Muscle, Skeletal; Rhabdomyosarcoma; Sarcoglycans; Solute Carrier Family 12, Member 2; Tandem Mass Spectrometry
PubMed: 35065666
DOI: 10.1186/s13395-021-00285-2 -
Journal of Functional Morphology and... Aug 2022The dystrophin-glycoprotein complex is a multimeric system made up of the sarcoglycan sub-complex, the sarcomplasmatic complex and the dystroglycans complex. The...
The dystrophin-glycoprotein complex is a multimeric system made up of the sarcoglycan sub-complex, the sarcomplasmatic complex and the dystroglycans complex. The sarcoglycan sub-complex stabilizes the sarcolemma during muscle activity and plays a role in force transduction. This protein system is also expressed in the muscle of non-human primates such as chimpanzees and baboons, and its expression changes depending on social ranking. In fact, previous data have shown that all muscle fibers of masseter and sternocleidomastoid muscles of chimpanzees and high- ranking baboons always express sarcoglycans, while middle- and low-ranking baboons are characterized by fibers that are negative for the sarcoglycan sub-complex. Given this information, the aim of the present work was to evaluate the expression of other proteins such as laminin, beta dystroglycan and dystrophin in the sternocleidomastoid muscle of high- and low-ranking baboons. The samples were processed by immunohistochemistry; results show that in high-ranking baboons, all tested proteins were always expressed while in low-ranking baboons, fibers that were negative for sarcoglycans and beta dystroglycan have been observed. No negative fibers for laminin and dystrophin have been found in low-ranking baboons suggesting that only the transmembrane proteins of the dystrophin glycoprotein complex change in their expression and that could be correlated to a phylogenetic arrangement.
PubMed: 36135420
DOI: 10.3390/jfmk7030062 -
Developmental Medicine and Child... Feb 2023To evaluate early dystonic features in children and adolescents with SGCE-myoclonus-dystonia.
AIM
To evaluate early dystonic features in children and adolescents with SGCE-myoclonus-dystonia.
METHOD
In this cross-sectional study, 49 patients (26 females and 23 males) with SGCE-myoclonus-dystonia (aged 15y 2mo, SD 12y) with childhood-onset (2y 10mo, SD 1y 10mo) dystonia were examined using a standardized video recorded protocol. Dystonia was rated using the Writer's Cramp and Gait Dystonia Rating Scales. Disability and impairment for handwriting and walking were also rated.
RESULTS
Dystonia was present at rest (n=1), posture (n=12), and during specific motor tasks (n=45) such as writing (n=35), walking (n=23), and running (n=20). Most children reported disability while performing these tasks. Early dystonic patterns were identified for writer's cramp and gait dystonia, the latter named the 'circular shaking leg', 'dragging leg', and 'hobby-horse gait' patterns. Sensory tricks were used by five and eight children to improve dystonia and myoclonus during writing and walking respectively. The rating scales accurately measured the severity of action dystonia and correlated with self-reported disability.
INTERPRETATION
Children with SGCE-myoclonus-dystonia show recognizable dystonic patterns and sensory tricks that may lead to an early diagnosis and timely therapeutic approach. Isolated writer's cramp is a key feature in childhood and should prompt SCGE analysis. The proposed action dystonia scales could be used to monitor disease course and response to treatment.
WHAT THIS PAPER ADDS
Most children with SGCE-myoclonus-dystonia got writer's cramp and had walking and running dystonia. Writer's cramp was a key feature and should prompt SGCE genetic investigation. 'Circular shaking leg', 'dragging leg', and 'hobby-horse gait' were recognized as early gait patterns. Children used sensory tricks to improve myoclonus and dystonia, suggesting common pathophysiological mechanisms. Action dystonia rating scales are valid tools to assess severity in children.
Topics: Child; Female; Humans; Male; Cross-Sectional Studies; Dystonia; Dystonic Disorders; Movement Disorders; Myoclonus; Sarcoglycans
PubMed: 35723607
DOI: 10.1111/dmcn.15298 -
Biochimica Et Biophysica Acta Feb 2014Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the... (Review)
Review
Dystrophin is a 427kDa sub-membrane cytoskeletal protein, associated with the inner surface membrane and incorporated in a large macromolecular complex of proteins, the dystrophin-associated protein complex (DAPC). In addition to dystrophin the DAPC is composed of dystroglycans, sarcoglycans, sarcospan, dystrobrevins and syntrophin. This complex is thought to play a structural role in ensuring membrane stability and force transduction during muscle contraction. The multiple binding sites and domains present in the DAPC confer the scaffold of various signalling and channel proteins, which may implicate the DAPC in regulation of signalling processes. The DAPC is thought for instance to anchor a variety of signalling molecules near their sites of action. The dystroglycan complex may participate in the transduction of extracellular-mediated signals to the muscle cytoskeleton, and β-dystroglycan was shown to be involved in MAPK and Rac1 small GTPase signalling. More generally, dystroglycan is view as a cell surface receptor for extracellular matrix proteins. The adaptor proteins syntrophin contribute to recruit and regulate various signalling proteins such as ion channels, into a macromolecular complex. Although dystrophin and dystroglycan can be directly involved in signalling pathways, syntrophins play a central role in organizing signalplex anchored to the dystrophin scaffold. The dystrophin associated complex, can bind up to four syntrophin through binding domains of dystrophin and dystrobrevin, allowing the scaffold of multiple signalling proteins in close proximity. Multiple interactions mediated by PH and PDZ domains of syntrophin also contribute to build a complete signalplex which may include ion channels, such as voltage-gated sodium channels or TRPC cation channels, together with, trimeric G protein, G protein-coupled receptor, plasma membrane calcium pump, and NOS, to enable efficient and regulated signal transduction and ion transport. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.
Topics: Animals; Dystrophin; Humans; Multiprotein Complexes; Muscle Contraction; Signal Transduction
PubMed: 24021238
DOI: 10.1016/j.bbamem.2013.08.023