High-frequency fatigue of skeletal muscle: role of extracellular Ca2+

Germinario, Elena; Esposito, Alessandra; Midrio, M; Peron, Samantha; Palade, Philip; Betto, Romeo; Danieli-Betto, Daniela

doi:10.1007/s00421-008-0796-5

Cited by 26 publications

(21 citation statements)

References 33 publications

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“…Muscle response was recorded by isometric force transducer (Grass FT03) connected to AT-MIO 16AD acquisition card (National Instruments). Data were analyzed by the specific module of the National Instruments LabView software (15). Tetanic stimulation was obtained by applying trains of supramaximal stimuli at 80-and 150-Hz frequency for soleus and EDL, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Individuals carrying the FSHD molecular defect, as well as normal controls, were clinically examined, using a standardized protocol, which generates the FSHD clinical score (21). The total score can range from 0, when no signs of muscle weakness are present, to 15, when all muscle groups tested are severely impaired (21). On this basis, all subjects were categorized as shown in Fig.…”

Section: R131 Altered Troponin T Splicing In Fshdmentioning

confidence: 99%

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Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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cioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca 2ϩ . We demonstrate that the decrease of Ca 2ϩ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. muscular dystrophy; aberrant splicing; muscle weakness; FRG1; troponin T FACIOSCAPULOHUMERAL MUSCULAR dystrophy (FSHD), one of the three most common hereditary myopathies, presents progressive atrophy and weakness of a highly specific set of muscle groups (10,11,31). FSHD is characterized by insidious onset and unpredictable progression with high variability of clinical expression, even within the same family (36,37,42). At present, no molecular mechanisms have been implicated in the development of these disease phenotypes, and no biological markers are available to define and monitor disease expression.More than 50 genes have been associated with muscular dystrophies (MD), whose genetic defects have been molecularly defined, and numerous animal models have been developed (30). In many cases, invaluable insights into disease mechanisms, structure and function of gene products, and approaches for therapeutic interventions have benefited from the study of animal models of the different MDs (1). In this context, FSHD is unique because no mutations have been found in any protein-coding gene. Instead, FSHD has been associated with reduction of the number of tandemly repeated 3.3-kb DNA segments (named D4Z4 repeats) located at the subtelomeric region of chromosome 4q (2, 44, 48). The number of D4Z4 repeats varies from 11 to 150 in the general population, whereas less than 11 repeats are present in sporadic and familial FSHD patients (48). The current model to explain FSHD is that the reduction of D4Z4 repeats in FSHD subjects initiates in...

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Section: Methodsmentioning

confidence: 99%

Section: R131 Altered Troponin T Splicing In Fshdmentioning

confidence: 99%

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Sancisi

Germinario

Esposito

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Studies have investigated how strain or contraction in whole skeletal muscles affects total uptake of glucose [8–10], lactate [11], phosphate [12], calcium [13, 14], and fatty acid [15]. However, they have predominantly elucidated the pharmacokinetic influence of activity-dependent metabolism on substrate uptake.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular drug transport under mechanical loading: Resonance between tissue function and uptake

Minisini

Edelman

2009

Journal of Controlled Release

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Dynamic architecture and motion in mechanically active target tissues can influence the pharmacokinetics of locally delivered agents. Drug transport in skeletal muscle under controlled mechanical loads was investigated. Static (0-20%) and cyclic (±2.5% amplitude, 0-20% mean, 1-3 Hz) strains and electrically paced isometric contractions (0.1-3 Hz, 0% strain) were applied to rat soleus incubated in 1 mM 20 kDa FITC-dextran. Dextran penetration, tissue porosity, and active force-length relationship over 0-20% strain correlated (r = 0.9-1.0), and all increased 1.5-fold from baseline at 0% to a maximum at 10% (L o ), demonstrating biologic significance of L o and impact of fiber size and distribution on function and pharmacokinetics. Overall penetration decreased but relative enhancement of penetration at L o increased with dextran size (4-150 kDa). Penetration increased linearly (0.084 mm/Hz) with cyclic stretch, demonstrating dispersion. Penetration increased with contraction rate by 1.5-fold from baseline to a maximum at 0.5 Hz, revealing architectural modulation of dispersion. Impact of architecture and dispersion on intramuscular transport was computationally modeled. Mechanical architecture and function underlie intramuscular pharmacokinetics and act in concert to effect resonance between optimal physiologic performance and drug uptake. Therapeutic management of characteristic function in tissue targets may enable a physiologic mechanism for controlled drug transport.

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“…Первым этапом инсулиномиметического действия ванадата является усиление поступления глюкозы в инсулинзависимые и некоторые инсулиннезависимые ткани [54]. Орованадат, перванадат и пероксованадат, добавленные в культуральную среду в низких концентрациях (10 -4 -10 -8 ммоль/л), стимулируют транспорт 2-[…”

Section: таблица формулы соединений (продолжение)unclassified

“…3 Н]-диокси-D-глюкозы в клетки фибробластов человека, миобластов линии L6, фибробластов линии 3T3-L1 и адипоцитов линии 3T3-L1 [54]. В скелетных [55], сердечной мышцах [56] и жировой ткани [57] крыс со стрептозотоциновым диабетом ванадат вызывает увеличение содержания и транслокацию в плазматическую мембрану специфического переносчика глюкозы ГЛЮТ-4.…”

Section: таблица формулы соединений (продолжение)unclassified

The vanadium compounds: chemistry, synthesys, insulinomimetic properties

et al. 2014

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The review considers the biological role of vanadium, its participation in various processes in humans and other mammals, and the anti-diabetic effect of its compounds. Vanadium salts have persistent hypoglycemic and antihyperlipidemic effects and reduce the probability of secondary complications in animals with experimental diabetes. The review contains a detailed description of all major synthesized vanadium complexes having antidiabetic activity. Currently, vanadium complexes with organic ligands are more effective and safer than the inorganic salts. Despite the proven efficacy of these compounds as the anti-diabetic agents in animal models, only one organic complex of vanadium is currently under the second phase of clinical trials. All of the considered data suggest that vanadium compound are a new promising class of drugs in modern pharmacotherapy of diabetes.

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High-frequency fatigue of skeletal muscle: role of extracellular Ca2+

Cited by 26 publications

References 33 publications

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

Intramuscular drug transport under mechanical loading: Resonance between tissue function and uptake

The vanadium compounds: chemistry, synthesys, insulinomimetic properties

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