Rates of ubiquitin conjugation increase when muscles atrophy, largely through activation of the N-end rule pathway

The rapid loss of muscle mass that accompanies many disease states, such as cancer or sepsis, is primarily a result of increased protein breakdown in muscle, and several observations have suggested an activation of the ubiquitin–proteasome system. Accordingly, in extracts of atrophying muscles from tumor-bearing or septic rats, rates of 125I-ubiquitin conjugation to endogenous proteins were found to be higher than in control extracts. On the other hand, in extracts of muscles from hypothyroid rats, where overall proteolysis is reduced below normal, the conjugation of 125I-ubiquitin to soluble proteins decreased by 50%, and treatment with triiodothyronine (T3) restored ubiquitination to control levels. Surprisingly, the N-end rule pathway, which selectively degrades proteins with basic or large hydrophobic N-terminal residues, was found to be responsible for most of these changes in ubiquitin conjugation. Competitive inhibitors of this pathway that specifically block the ubiquitin ligase, E3α, suppressed most of the increased ubiquitin conjugation in the muscle extracts from tumor-bearing and septic rats. These inhibitors also suppressed ubiquitination in normal extracts toward levels in hypothyroid extracts, which showed little E3α-dependent ubiquitination. Thus, the inhibitors eliminated most of the differences in ubiquitination under these different pathological conditions. Moreover, 125I-lysozyme, a model N-end rule substrate, was ubiquitinated more rapidly in extracts from tumor-bearing and septic rats, and more slowly in those from hypothyroid rats, than in controls. Thus, the rate of ubiquitin conjugation increases in atrophying muscles, and these hormone- and cytokine-dependent responses are in large part due to activation of the N-end rule pathway.

The whistle and the rattle: the design of sound producing muscles.

Vertebrate sound producing muscles often operate at frequencies exceeding 100 Hz, making them the fastest vertebrate muscles. Like other vertebrate muscle, these sonic muscles are "synchronous," necessitating that calcium be released and resequestered by the sarcoplasmic reticulum during each contraction cycle. Thus to operate at such high frequencies, vertebrate sonic muscles require extreme adaptations. We have found that to generate the "boatwhistle" mating call (approximately 200 Hz), the swimbladder muscle fibers of toadfish have evolved (i) a large and very fast calcium transient, (ii) a fast crossbridge detachment rate, and (iii) probably a fast kinetic off-rate of Ca2+ from troponin. The fibers of the shaker muscle of rattlesnakes have independently evolved similar traits, permitting tail rattling at approximately 90 Hz.

Functional protection of dystrophic mouse (mdx) muscles after adenovirus-mediated transfer of a dystrophin minigene.

Fast skeletal muscles of mdx (X chromosome-linked muscular dystrophy) mice were injected after birth with a recombinant adenovirus containing a minidys- trophin gene, a 6.3-kbp cDNA coding for the N- and C-terminal ends of dystrophin. Adult muscles were challenged by forced lengthening during tetanic contractions. Stretch-induced mechanical and histological damages were much reduced in injected muscles, in direct proportion of the Miniber of fibers expressing minidystrophin. Damaged fibers were preferentially found among minidystrophin-negative regions. Minidystrostrophin confers an important functional and structural protection of limb muscles against high mechanical stress, even after a partial somatic gene transfer.

Efeito de diferentes intensidades do treinamento de força nos ganhos de força máxima e hipertrofia muscular

O presente estudo investigou o efeito de diferentes intensidades do treinamento de força (TF), aplicadas com volume total de treino (VTT) equalizado, nos ganhos de força dinâmica máxima (1RM) e massa muscular dos membros superiores e inferiores. Trinta voluntários do sexo masculino, com idade entre 18 e 30 anos, participaram de 12 semanas de TF com uma frequência semanal de duas sessões. Foi utilizado um protocolo de treinamento unilateral com um dos lados do corpo realizando o exercício com intensidade equivalente a 20% 1RM (G20) e o lado contralateral utilizando uma das três intensidades 40%, 60% ou 80% 1RM (G40, G60 e G80, respectivamente). O grupo G20 realizava três séries compostas de repetições até a falha concêntrica e o VTT era calculado e replicado para os demais grupos. A força dinâmica máxima e a área de secção transversa (AST) dos músculos flexores do cotovelo e do vasto lateral foram avaliadas nos momentos pré, 6 semanas e pós-treinamento. Os resultados demonstraram que os grupos G40, G60 e G80 apresentaram ganhos similares de AST (25%, 25,1% e 25%, flexores do cotovelo e 20,5%, 20,4% e 19,5% vasto lateral, respectivamente, p<0,05). Somente o grupo G80 demonstrou diferença significante com o grupo G20 na comparação do período pós-treinamento (25% e 14,4%, respectivamente para os flexores do cotovelo e 19,5% e 7,9%, respectivamente para vasto lateral, p<0,05). Para os ganhos de 1RM o grupo G80 demonstrou maiores aumentos após 12 semanas de TF para a flexão unilateral do cotovelo na posição em pé (54,2% p<0,05) e para o leg press 45º os grupos G60 e G80 demonstraram os maiores aumentos (55,4% e 45,7%, respectivamente, p<0,05). Assim, quando o VTT foi equalizado entre diferentes intensidades (40, 60 e 80% 1RM) os ganhos da AST tanto dos flexores do cotovelo quanto o vasto lateral foram semelhantes e a intensidade de 20% 1RM não causou aumento significante da AST. No que diz respeito a força muscular as intensidades mais elevadas (60% e 80% 1RM) foram superiores em promover ganhos de força do que as demais intensidades utilizadas. Esses dados sugerem que ao equalizar o VTT os ganhos de massa muscular são semelhantes para as intensidades de treinamento entre 40- 80% 1RM. Além disso, a intensidade de 20% 1RM, mesmo com o VTT equalizado com as intensidades maiores, não promove aumentos de massa muscular para ambos os segmentos corporais. Por outro lado, intensidades altas de treinamento produzem os maiores ganhos de força máxima em membros superiores e inferiores

Dysfunction of respiratory muscles in critically ill patients on the intensive care unit.

Muscular weakness and muscle wasting may often be observed in critically ill patients on intensive care units (ICUs) and may present as failure to wean from mechanical ventilation. Importantly, mounting data demonstrate that mechanical ventilation itself may induce progressive dysfunction of the main respiratory muscle, i.e. the diaphragm. The respective condition was termed 'ventilator-induced diaphragmatic dysfunction' (VIDD) and should be distinguished from peripheral muscular weakness as observed in 'ICU-acquired weakness (ICU-AW)'. Interestingly, VIDD and ICU-AW may often be observed in critically ill patients with, e.g. severe sepsis or septic shock, and recent data demonstrate that the pathophysiology of these conditions may overlap. VIDD may mainly be characterized on a histopathological level as disuse muscular atrophy, and data demonstrate increased proteolysis and decreased protein synthesis as important underlying pathomechanisms. However, atrophy alone does not explain the observed loss of muscular force. When, e.g. isolated muscle strips are examined and force is normalized for cross-sectional fibre area, the loss is disproportionally larger than would be expected by atrophy alone. Nevertheless, although the exact molecular pathways for the induction of proteolytic systems remain incompletely understood, data now suggest that VIDD may also be triggered by mechanisms including decreased diaphragmatic blood flow or increased oxidative stress. Here we provide a concise review on the available literature on respiratory muscle weakness and VIDD in the critically ill. Potential underlying pathomechanisms will be discussed before the background of current diagnostic options. Furthermore, we will elucidate and speculate on potential novel future therapeutic avenues.

Anatomy improv'd and illustrated with regard to the uses thereof in designing : not only laid down from an examen of the bones and muscles of the human body, but also demonstrated and exemplified from the most celebrated antique statues in Rome : exhibited in a great number of copper plates, with all the figures in various views : intended originally for ye use of the Royal French Academy of Painting and Sculpture /

Re-engraved by Michael van der Gucht and others after the original edition published at Rome in 1691.

What the brain tells the muscles /

Mode of access: Internet.

An account of a new method of treating diseases of the joints of the knee and elbow : : in a letter to Mr. Percival Pott /

Mode of access: Internet.

Premier mémoire sur le traitement des déviations de l'épine par la section des muscles du dos; lu a l'Académie des sciences ... /

Mode of access: Internet.

Anatomical remembrancer or complete pocket anatomist : containing a concise description of the bones, ligaments, muscles, and viscera, the nerves ...

Mode of access: Internet.

The Dublin dissector, or manual of anatomy : comprissing a concise description of the bones, muscles, vessels, nerves and viscera, also the relative anatomy of the different regions of the human body.../

Mode of access: Internet.

Maladies des organes du mouvement : os, muscles, etc., en général /

Las h. de grab. son litogr.: "Emile Beau ad nat. lith.", "Imp. Lemercier"

Les lois du mouvement énergétique dans les muscles en contraction volontaire statique; nouvelle méthode pour l'étude des phénomènes physico-chimiques de la respiration ...

Thèse--Univ. de Paris.

Myo-graphie ou Description des muscles du corps humain /

Texto con caja.