Skinned single fibers from normal and dystrophin‐deficient dogs incur comparable stretch‐induced force deficits

Childers, Martin K.; Staley, Jerry T.; Kornegay, Joe N.; McDonald, Kerry S.

doi:10.1002/mus.20298

Cited by 10 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5d. In contrast, dystrophic slow fibres did not show reduced force in comparison with wild-type fibres, as shown previously 16 (data not shown). A similar measurement on the single skinned fibres of the tibialis cranialis and sartorius of Vaccin and Valium (06A and (07A) showed a similar trend, but the increase in force of contraction was modest and not statistically significant (data not shown).…”

Section: Enhancement Of Contraction Forcesupporting

confidence: 89%

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Sampaolesi

Blot

D’Antona

et al. 2006

Nature

674

569

View full text Add to dashboard Cite

Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.

show abstract

Section: Enhancement Of Contraction Forcesupporting

confidence: 89%

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Sampaolesi

Blot

D’Antona

et al. 2006

Nature

674

569

View full text Add to dashboard Cite

show abstract

“…While our preliminary data must be interpreted cautiously until additional biological replicates with isogenic controls are completed, the strong signal obtained from the “stress assay” (Fig 5D) supports the idea that dystrophin deficiency renders the cardiomyocyte abnormally vulnerable to mechanical stress. This idea is supported by a line of evidence in dystrophin-deficient skeletal muscle(Allen, Zhang, & Whitehead, 2010; Childers et al, 2002; Childers et al, 2001; Childers, Staley, Kornegay, & McDonald, 2005; Deconinck & Dan, 2007; Grounds, 2008) and to a lesser extent in cardiac muscle(De Pooter, Vandeweghe, Vonck, Loth, & Geraedts, 2012; Phillips & Quinlivan, 2008). While the concept of increased susceptibility to stress might be considered a foregone conclusion, to our knowledge, stress assays conducted in iPS-derived DMD cardiomyocytes have not yet been reported.…”

Section: 4 Discussionmentioning

confidence: 80%

Dystrophin-deficient cardiomyocytes derived from human urine: New biologic reagents for drug discovery

et al. 2014

Self Cite

View full text Add to dashboard Cite

The ability to extract somatic cells from a patient and reprogram them to pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem cells (iPSCs) have been employed to generate beating cardiomyocytes from a patient's skin or blood cells. Here, iPSC methods were used to generate cardiomyocytes starting from the urine of a patient with Duchenne muscular dystrophy (DMD). Urine was chosen as a starting material because it contains adult stem cells called urine-derived stem cells (USCs). USCs express the canonical reprogramming factors c-myc and klf4, and possess high telomerase activity. Pluripotency of urine-derived iPSC clones was confirmed by immunocytochemistry, RT-PCR and teratoma formation. Urine-derived iPSC clones generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes using a series of small molecules in monolayer culture. Results indicate that cardiomyocytes retain the DMD patient's dystrophin mutation. Physiological assays suggest that dystrophin-deficient cardiomyocytes possess phenotypic differences from normal cardiomyocytes. These results demonstrate the feasibility of generating cardiomyocytes from a urine sample and that urine-derived cardiomyocytes retain characteristic features that might be further exploited for mechanistic studies and drug discovery.

show abstract

“…Mdx mice (dystrophin deficient) and wild-type littermates were obtained under approved protocol number F07-008, held by Dr. Judy Anderson, Faculty of Biological Sciences, University of Manitoba [42], [43]. Canine airway smooth muscle cells were cultured from trachealis muscle of golden retriever muscular dystrophy (GRMD) or healthy littermates [26]–[28]. Canine tissues were obtained from Dr. MK Childers, Wake Forest University Health Sciences, Winston-Salem, NC, USA.…”

Section: Methodsmentioning

confidence: 99%

Role of Dystrophin in Airway Smooth Muscle Phenotype, Contraction and Lung Function

et al. 2014

View full text Add to dashboard Cite

Dystrophin links the transmembrane dystrophin-glycoprotein complex to the actin cytoskeleton. We have shown that dystrophin-glycoprotein complex subunits are markers for airway smooth muscle phenotype maturation and together with caveolin-1, play an important role in calcium homeostasis. We tested if dystrophin affects phenotype maturation, tracheal contraction and lung physiology. We used dystrophin deficient Golden Retriever dogs (GRMD) and mdx mice vs healthy control animals in our approach. We found significant reduction of contractile protein markers: smooth muscle myosin heavy chain (smMHC) and calponin and reduced Ca2+ response to contractile agonist in dystrophin deficient cells. Immunocytochemistry revealed reduced stress fibers and number of smMHC positive cells in dystrophin-deficient cells, when compared to control. Immunoblot analysis of Akt1, GSK3β and mTOR phosphorylation further revealed that downstream PI3K signaling, which is essential for phenotype maturation, was suppressed in dystrophin deficient cell cultures. Tracheal rings from mdx mice showed significant reduction in the isometric contraction to methacholine (MCh) when compared to genetic control BL10ScSnJ mice (wild-type). In vivo lung function studies using a small animal ventilator revealed a significant reduction in peak airway resistance induced by maximum concentrations of inhaled MCh in mdx mice, while there was no change in other lung function parameters. These data show that the lack of dystrophin is associated with a concomitant suppression of ASM cell phenotype maturation in vitro, ASM contraction ex vivo and lung function in vivo, indicating that a linkage between the DGC and the actin cytoskeleton via dystrophin is a determinant of the phenotype and functional properties of ASM.

show abstract

Skinned single fibers from normal and dystrophin‐deficient dogs incur comparable stretch‐induced force deficits

Cited by 10 publications

References 19 publications

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

Dystrophin-deficient cardiomyocytes derived from human urine: New biologic reagents for drug discovery

Role of Dystrophin in Airway Smooth Muscle Phenotype, Contraction and Lung Function

Contact Info

Product

Resources

About