TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

Call, Jarrod A.; Ervasti, James M.; Lowe, Dawn A.

doi:10.1152/japplphysiol.00248.2011

Cited by 21 publications

(16 citation statements)

References 36 publications

(65 reference statements)

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“…Our measured resilience also demonstrated excellent correlation with mechanical restoration of dystrophic muscles treated with Mini-Dys 29 and Micro-Dys 25; 39 (Fig. 7b, R = 0.99).…”

Section: Discussionsupporting

confidence: 58%

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Impacts of Dystrophin and Utrophin Domains on Actin Structural Dynamics: Implications for Therapeutic Design

Lin

Próchniewicz

Henderson

et al. 2012

Journal of Molecular Biology

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We have used time-resolved phosphorescence anisotropy (TPA) of actin to evaluate domains of dystrophin and utrophin, with implications for gene therapy in muscular dystrophy. Dystrophin and its homolog utrophin bind to cytoskeletal actin to form mechanical linkages that prevent muscular damage. Because these proteins are too large for most gene therapy vectors, much effort is currently devoted to smaller constructs. We previously used TPA to show that dystrophin and utrophin both have a paradoxical effect on actin rotational dynamics -- restricting amplitude while increasing rate, thus increasing resilience, with utrophin more effective than dystrophin. Here we have evaluated individual domains of these proteins. We found that a “mini-dystrophin,” lacking one of the two actin-binding domains, is less effective than dystrophin in regulating actin dynamics, correlating with its moderate effectiveness in rescuing the dystrophic phenotype in mice. In contrast, we found that a “micro-utrophin,” with more extensive internal deletions, is as effective as full-length dystrophin in the regulation of actin dynamics. Each of utrophin’s actin-binding domains promotes resilience in actin, while dystrophin constructs require the presence of both actin-binding domains and the CT domain for full function. This work supports the use of a utrophin template for gene or protein therapy designs. Resilience of the actin-protein complex, measured by TPA, correlates remarkably well with previous reports of functional rescue by dystrophin and utrophin constructs in mdx mice. We propose the use of TPA as an in vitro method to aid in the design and testing of emerging gene therapy constructs.

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“…Our measured resilience also demonstrated excellent correlation with mechanical restoration of dystrophic muscles treated with Mini-Dys 29 and Micro-Dys 25; 39 (Fig. 7b, R = 0.99).…”

Section: Discussionsupporting

confidence: 58%

“…This micro-TRIT (designated UtrΔ R4-21, because the segment from STR4 through STR 21 have been deleted, leaving only 4 STRs) has previously been tested in mouse models. 38; 39 TPA data shows that Micro-Utr restricts actin rotational amplitude and increases rate with comparable cooperativity as full-length dystrophin or utrophin (Fig. 5b&c).…”

Section: Resultsmentioning

confidence: 82%

Impacts of Dystrophin and Utrophin Domains on Actin Structural Dynamics: Implications for Therapeutic Design

Lin

Próchniewicz

Henderson

et al. 2012

Journal of Molecular Biology

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“…μUtr-glycoprotein complexes with actin binding affinity were established at the sarcolemma within the therapeutic range previously demonstrated to be effective against dystrophy. Similar levels of functional improvement were observed in studies using mdx:utrn -/-mice [169], providing proof-of-concept that direct protein delivery can be achieved through injectable TATμUtr and could provide real therapeutic benefit in DMD. However, numerous challenges face its transition into clinical trials, especially given that frequent, high dosage injections may be required for human benefit; an approach likely to provoke a severe immune response.…”

Section: Utrophin Upregulationsupporting

confidence: 73%

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Fairclough

Perkins²,

Davies³

2012

CGT

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DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy. Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restricted to management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 with the discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology of DMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towards the identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition to gene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacological approaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs are also being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect, including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue, utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB, TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements. There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulating Ca2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tackling the complex pathogenesis of this multifaceted disorder.

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“…Immediately following testing of the anterior crural muscles, the left common peroneal nerve was severed and testing of the posterior crural muscles began. Contraction of this muscle group was elicited by stimulating the sciatic nerve (7). Peak-isometric torque was determined during a 200-ms stimulation with varying voltages (3.0 to 7.0 V) at 300 Hz using 1-ms square-wave pulses.…”

Section: Methodsmentioning

confidence: 99%

Adaptations of Mouse Skeletal Muscle to Low-Intensity Vibration Training

McKeehen

Novotny

Baltgalvis

et al. 2013

Medicine &Amp; Science in Sports &Amp; Exercise

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Purpose We tested the hypothesis that low intensity vibration training in mice improves contractile function of hindlimb skeletal muscles and promotes exercise-related cellular adaptations. Methods We subjected C57BL/6J mice to 6 wk, 5 d·wk−1, 15 min·d−1 of sham or low intensity vibration (45 Hz, 1.0 g) while housed in traditional cages (Sham-Active, n=8; Vibrated-Active, n=10) or in small cages to restrict physical activity (Sham-Restricted, n=8; Vibrated-Restricted, n=8). Contractile function and resistance to fatigue were tested in vivo (anterior and posterior crural muscles) and ex vivo on the soleus muscle. Tibialis anterior and soleus muscles were evaluated histologically for alterations in oxidative metabolism, capillarity, and fiber types. Epididymal fat pad and hindlimb muscle masses were measured. Two-way ANOVAs were used to determine effects of vibration and physical inactivity. Results Vibration training resulted in a 10% increase in maximal isometric torque (P=0.038) and 16% faster maximal rate of relaxation (P=0.030) of the anterior crural muscles. Posterior crural muscles were unaffected by vibration, with the exception of greater rates of contraction in Vibrated-Restricted mice compared to Vibrated-Active and Sham-Restricted mice (P=0.022). Soleus muscle maximal isometric tetanic force tended to be greater (P=0.057) and maximal relaxation was 20% faster (P=0.005) in Vibrated compared to Sham mice. Restriction of physical activity induced muscle weakness but was not required for vibration to be effective in improving strength or relaxation. Vibration training did not impact muscle fatigability or any indicator of cellular adaptation investigated (P≥0.431). Fat pad but not hindlimb muscle masses were affected by vibration training. Conclusion Vibration training in mice improved muscle contractility, specifically strength and relaxation rates, with no indication of adverse effects to muscle function or cellular adaptations.

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TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

Abstract: Call JA, Ervasti JM, Lowe DA. Tat-Utrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice.

Cited by 21 publications

References 36 publications

Impacts of Dystrophin and Utrophin Domains on Actin Structural Dynamics: Implications for Therapeutic Design

Impacts of Dystrophin and Utrophin Domains on Actin Structural Dynamics: Implications for Therapeutic Design

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Adaptations of Mouse Skeletal Muscle to Low-Intensity Vibration Training

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