Plasma thyroxine levels in Duchenne muscular dystrophy

Some young Duchenne muscular dystrophy (DMD) patients (3-7 years) had total thyroxine (T4) levels and T4 to thyroxine binding globulin (TBG) ratios above the normal range and significantly increased free thyroxine indices (fT4I) which, however, remained within the normal range. Older DMD patients (7-11 years) had T4 and TBG levels and fT4I similar to normal. In both DMD groups the thyroxine binding index (TBI) values were in the normal range.     

Plasma thyroxine levels in Duchenne muscular dystrophy

Summary Some young Duchenne muscular dystrophy (DMD) patients (3–7 years) had total thyroxine (T₄) levels and T₄ to thyroxine binding globulin (TBG) ratios above the normal range and significantly increased free thyroxine indices (fT₄I) which, however, remained within the normal range. Older DMD patients (7–11 years) had T₄ and TBG levels and fT₄I similar to normal. In both DMD groups the thyroxine binding index (TBI) values were in the normal range.     

Dystrophin and the integrity of the sarcolemma in Duchenne muscular dystrophy

It is suggested that in Duchenne muscular dystrophy the absence of dystrophin, which is probably a cytoskeletal protein underlying the sarcolemma, causes changes in stretch-activated cation channels rather than direct mechanical tearing of the surface membrane.     

Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy

Bone morphogenetic proteins (BMPs) are important extracellular cytokines that play critical roles in embryogenesis and tissue homeostasis. BMPs signal via transmembrane type I and type II serine/threonine kinase receptors and intracellular Smad effector proteins. BMP signaling is precisely regulated and perturbation of BMP signaling is connected to multiple diseases, including musculoskeletal diseases. In this review, we will summarize the recent progress in elucidation of BMP signal transduction, how overactive BMP signaling is involved in the pathogenesis of heterotopic ossification and Duchenne muscular dystrophy, and discuss possible therapeutic strategies for treatment of these diseases.     

Intracisternal A type particles of the extraocular muscle of hereditary muscular dystrophy mouse

Summary Intracisternal A type virus (IA) particles were observed in the extraocular muscle fiber of hereditary muscular dystrophy mouse. The particles appeared approximately 65–75 m in diameter, with electron lucent cores.     

Intracisternal A type particles of the extraocular muscle of hereditary muscular dystrophy mouse.

Intracisternal A type virus (IA) particles were observed in the extraocular muscle fiber of hereditary muscular dystroph mouse. The particles appeared approximately 65-75 mmu in diameter, with electron lucent cores.     

Human sex-linked muscular dystrophy: Kinetics of the isometric twitch

Résumé Les propriétés mécaniques du muscle adducteur du pouce atteint de dystrophie musculaire de type Duchenne ont été étudiées in situ chez 15 malades. La force produite par la secousse isométrique et le tétanos isométrique est réduite dans tous les cas. Le temps de contraction de la secousse isométrique et son temps de relaxation sont légèrement supérieurs aux valeurs de contrôle. Cette différence disparait au cours de la stimulation répétée du nerf à 2/sec. Ces observations montrent que l'activité ATPase de la myosine (déterminant la vitesse de contraction) et le processus de séquestration du Ca⁺⁺ myoplasmique dans le réticulum sarcoplasmique (déterminant la vitesse de relaxation) ne sont pas altérés de façon irréversible dans la dystrophie musculaire de Duchenne.

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On leave from the Neurology Clinic of the Medical Academy, Warsaw.

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This work was supported by the Muscular Dystrophy Associations of America Inc. and by the Fonds de la Recherche Scientifique Médicale.     

Revisiting the role of mitochondria in spinal muscular atrophy

Cellular and Molecular Life Sciences - Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor...     

Role of muscular disuse in the genesis of fibrillation in denervated muscle

Riassunto Nei muscoli soleo-gastrocnemio di ratto la denervazione ha determinato insorgenza della fibrillazione dopo 60–66 h. Se eseguita dopo qualche giorno di disuso muscolare (conseguente a tenotomia, sezione del midollo spinale, immobilizzazione dell'arto) la denervazione ha determinato insorgenza della fibrillazione molto più precocemente, con un intervallo minimo di 24 h. Viene suggerito che nella genesi della fibrillazione dopo denervazione, il disuso muscolare abbia un ruolo importante.     

Glutamate oxaloacetate transaminase (GOT) in thedy 2J genotypes of C57BL/6J mice: Possible involvement of regulatory defect in muscular dystrophy

Summary The GOT mitochondrial isozyme of heterozygote and homozygote muscular dystrophy (dy^2J) genotypes is affected during development prior to the expression of dystrophy in homozygotes, dy^2J/dy^2J.This research was supported by a Natural Science and Engineering Research Council Canada grant to S.M.S.     

A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action of parachlorophenylalanine by 5-hydroxytroptophan

Summary An acute reduction in the synaptic availability of serotonin (5HT) by p-chlorophenlalanine (PCPA) nullifies the decrease in the density of cortical beta adrenoceptors caused by desipramine (DMI) but does not appreciably alter the attenuation of the norepinephrine (NE) sensitive adenylate cyclase. The analysis of competition-binding curves of [³H]-dihydroalprenolol shows that the affinity of the agonist (–)-isoproterenol for cortical beta adrenoceptors is profoundly reduced following PCPA. This reduction in agonist affinity is enhanced by DMI. Resupplying 5HT by by-passing trptophan hydroxylase inhibition, by administering 5-hydroxytryptophan, converts a DMI non-responsive to a DMI responsive beta adrenoceptor population and shifts the markedly decreased agonist affinity towards the affinity values found in control preparations. The results demonstrate the pivotal role of 5HT in the regulation of the density and agonist affinity characteristics of cortical beta adrenoceptors and contribute to the scientific basis of the serotonin-norepinephrine link hypothesis of affective disorders.Acknowledgments. This work was supported by USPHS grant MH-29228 and the Tennessee Department of Mental Health and Mental Retardation. Present address of L. R. Sterank: NOVA Pharmaceutical Corporation, Baltimore (MD 21228, USA).     

AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism

The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known upstream kinases, LKB1, Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle. Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008     

Double deficiency of cathepsins B and L results in massive secretome alterations and suggests a degradative cathepsin-MMP axis

Endolysosomal cysteine cathepsins functionally cooperate. Cathepsin B (Ctsb) and L (Ctsl) double-knockout mice die 4 weeks after birth accompanied by (autophago-) lysosomal accumulations within neurons. Such accumulations are also observed in mouse embryonic fibroblasts (MEFs) deficient for Ctsb and Ctsl. Previous studies showed a strong impact of Ctsl on the MEF secretome. Here we show that Ctsb alone has only a mild influence on extracellular proteome composition. Protease cleavage sites dependent on Ctsb were identified by terminal amine isotopic labeling of substrates (TAILS), revealing a prominent yet mostly indirect impact on the extracellular proteolytic cleavages. To investigate the cooperation of Ctsb and Ctsl, we performed a quantitative secretome comparison of wild-type MEFs and Ctsb ^?/? Ctsl ^?/? MEFs. Deletion of both cathepsins led to drastic alterations in secretome composition, highlighting cooperative functionality. While many protein levels were decreased, immunodetection corroborated increased levels of matrix metalloproteinase (MMP)-2. Re-expression of Ctsl rescues MMP-2 abundance. Ctsl and to a much lesser extent Ctsb are able to degrade MMP-2 at acidic and neutral pH. Addition of active MMP-2 to the MEF secretome degrades proteins whose levels were also decreased by Ctsb and Ctsl double deficiency. These results suggest a degradative Ctsl—MMP-2 axis, resulting in increased MMP-2 levels upon cathepsin deficiency with subsequent degradation of secreted proteins such as collagen α-1 (I).     

The role of muscle in determining growth and size in teleost fish

Summary Rapid growth to large size in fish results from a sustained recruitment of new fibres into their axial series of myomeres. Cessation of recruitment at a small fish size leads to slow growth and a small final size of the fish. Fibre growth dynamics of fishes evidently govern growth and size through fibres' surface area to length ratios, which control their nutrient assimilation rates.     

The role of myosin phosphorylation in the contraction-relaxation cycle of smooth muscle

Summary Considerable evidence from a variety of experimental procedures indicates that the phosphorylation of myosin is involved in the regulation of contractile activity in smooth muscle. Phosphorylation of the 20,000-dalton myosin light chains is required to initiate crossbridge cycling and this is consistent with the observation that the actin-activated Mg²⁺-ATPase activity of myosin is phosphorylation-dependent. In the simplest interpretation of this process it may be proposed that phosphorylation acts as an on-off switch. Clearly this cannot explain the observed complexity of smooth muscle contractile behavior and such may imply either that additional mechanisms are involved or that the role of myosin phosphorylation is not fully appreciated. Recently it has been shown that monomeric smooth muscle myosin can exist in a folded and an extended conformation and that each form is characterized by distinct enzymatic properties. Under appropriate solvent conditions phosphorylation of myosin favors the extended conformation. It is tentatively suggest that this, or an analogous, transition might be involved in the regulation of the smooth muscle contractile apparatus, and this possibility is discussed.The authors are supported by grants HL 23615 and HL 20984 from the National Institutes of Health.     

The muscle ultrastructure: a structural perspective of the sarcomere

Muscle ultrastructure is characterised by a complex arrangement of many protein-protein interactions. The sarcomere is the basic repeating unit of muscle, formed by two transverse filament systems: the thick and thin filaments. While actin and myosin are the main contractile elements of the sarcomere, other proteins act as scaffolds, control ultrastructure composition, regulate muscle contraction, and transmit tension between sarcomeres and hence to the whole myofibril. Elucidation of the structures of muscle proteins by X-ray crystallography and nuclear magnetic resonance spectroscopy has been essential in understanding muscle contraction, enabling us to relate biological to structural information. These structures reveal how components of the muscle interact, how different factors influence conformational changes within these proteins, and how mutant muscle proteins may interfere with the regulatory fine-tuning of the contractile machinery, hence leading to disease in some cases. Here, structures solved within the sarcomere have been reviewed in order to put the numerous components into context.Received 28 June 2004; received after revision 25 July 2004; accepted 28 July 2004