Increase in ubiquitin-protein conjugates concomitant with the increase in proteolysis in rat skeletal muscle during starvation and atrophy denervation (original) (raw)
Related papers
Biochemical Journal, 1995
Most of the increased protein degradation in muscle atrophy caused by starvation and denervation is due to activation of a non-lysosomal ATP-dependent proteolytic process. To determine whether expression of the ubiquitin-proteasome-dependent pathway is activated in atrophying muscles, we measured the levels of mRNA for ubiquitin (Ub) and proteasome subunits, and Ub content. After rats had been deprived of food for 1 or 2 days, the concentration of the two polyubiquitin (polyUb) transcripts increased 2-4-fold in the pale extensor digitorum longus muscle and 1-2.5-fold in the red soleus, whereas total muscle RNA and total mRNA content fell by 50%. After denervation of the soleus, there was a progressive 2-3-fold increase in polyUb mRNA for 1-3 days, whereas total RNA content fell. On starvation or denervation, Ub concentration in the muscles also rose by 60-90%. During starvation, polyUb mRNA levels also increased in heart, but not in liver, kidney, spleen, fat, brain or testes. Altho...
Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting
American Journal of Physiology-Cell Physiology, 1999
The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% ( P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E214k, were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO3did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adr...
Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting
Reproduction Nutrition Development, 1994
― Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca 2 +-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically analyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca 2 +-dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fasting and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed. skeletal muscle / protein breakdown / ubiquitin / proteasome Résumé ― Régulation de la protéolyse musculaire ATP-ubiquitine-dépendante au cours des états cataboliques. La protéolyse joue un rôle majeur dans le contrôle de la croissance ou de l'atrophie musculaire. Cependant, ses mécanismes de régulation par les nutriments, les facteurs hormonaux ou l'activité musculaire sont encore peu connus. Cette revue analyse de façon critique les différentes techniques disponibles pour étudier la dégradation des protéines musculaires, et le rôle des 3 systèmes protéolytiques majeurs bien caractérisés dans ce tissu, c'est-à-dire la voie lysosomaie, Ca 2 +-dépendante et A TP-ubiquitine-dépendante. La protéolyse A 7'P-uo;qu;f<ne-dépendanfe est plus particulièrement évoquée, car des travaux récents suggèrent que cette voie serait responsable de la dégradation des protéines contractiles majeures au cours de multiples états cataboliques chez les rongeurs. Contrairement aux systèmes protéolytiques lysosomal et Ca 2 ·-dépendant, la protéolyse ATP-ubiquitinedépendante est systématiquement influencée par les manipulations nutritionnelles (jeûne, régime déficient en protéines), l'activité et l'inactivité musculaire (dénervation, apesanteur simulée), et de nombreux états pathologiques (infections, cancers, traumatismes, acidose). La régulation hormonale, les substrats possibles, l'étape limitante et la coordination fonctionnelle de cette voie de la protéolyse avec les autres systèmes protéolytiques sont discutés. muscle squelettique / protéolyse / ubiquitine lprotéasome
The role of ubiquitin–proteasome-dependent proteolysis in the remodelling of skeletal muscle
Proceedings of The Nutrition Society, 2004
In skeletal muscle, as in any mammalian tissue, protein levels are dictated by relative rates of protein synthesis and breakdown. Recent studies have shown that the ubiquitin-proteasomedependent proteolytic pathway is mainly responsible for the breakdown of myofibrillar proteins. In this pathway proteins that are to be degraded are first tagged with a polyubiquitin degradation signal. Ubiquitination is performed by the ubiquitin-activating enzyme, ubiquitinconjugating enzymes and ubiquitin-protein ligases, which are responsible for the recognition of specific substrates. Polyubiquitinated protein substrates are then specifically recognised and degraded by the 26S proteasome. The present review focuses on: (1) the mechanisms of ubiquitination-deubiquitination that make the system highly selective; (2) the mechanisms of proteolysis in skeletal muscle. In particular, the role of the system in the remodelling of skeletal muscle during exercise and disuse and in recovery or regeneration that prevails during post-atrophic conditions is reviewed.
Ubiquitin-proteasome-dependent proteolysis in skeletal muscle
Reproduction Nutrition Development, 1998
The ubiquitin-proteasome proteolytic pathway has recently been reported to be of major importance in the breakdown of skeletal muscle proteins. The first step in this pathway is the covalent attachment of polyubiquitin chains to the targeted protein. Polyubiquitylated proteins are then recognized and degraded by the 26S proteasome complex. In this review, we critically analyse recent findings in the regulation of this pathway, both in animal models of muscle wasting and in some human diseases. The identification of regulatory steps of ubiquitin conjugation to protein substrates and/or of the proteolytic activities of the proteasome should lead to new concepts that can be used to manipulate muscle protein mass. Such concepts are essential for the development of anti-cachectic therapies for many clinical situations. @ Inra/Elsevier, Paris skeletal muscle / protein breakdown / ubiquitin / proteasome Résumé -Protéolyse musculaire ubiquitine-protéasome dépendante. Il a été récemmment démontré que la protéolyse ubiquitine-protéasome dépendante joue un rôle majeur dans la dégradation des protéines musculaires. La première étape de cette voie protéolytique correspond à la fixation covalente de chaînes polyubiquitylées sur les substrats protéiques. Ces protéines polyubiquitylées sont ultérieurement spécifiquement reconnues et dégradées par le protéasome 26S. Les derniers progrès accomplis dans la compréhension de la régulation de ce système dans les modèles animaux de fontes protéiques musculaires, et dans certaines situations cliniques, sont analysés de façon critique dans cette revue bibliographique. L'identification d'étapes régulatrices de 1'ubiquitylation des substrats protéiques, et/ou des activités protéolytiques du protéasome, devrait conduire à de nouveaux concepts utilisables pour manipuler le dépôt des protéines musculaires. En particulier, ces concepts sont indispensables au développement de traitements anti-cachectiques dans de nombreuses situations cliniques. @ Inra/Elsevier,
The ubiquitin–proteasome system and skeletal muscle wasting
Essays in Biochemistry, 2005
The ubiquitin-proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin-protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.
The Journal of Physiological Sciences, 2020
Skeletal muscle is one of the most abundant and highly plastic tissues. The ubiquitin–proteasome system (UPS) is recognised as a major intracellular protein degradation system, and its function is important for muscle homeostasis and health. Although UPS plays an essential role in protein degradation during muscle atrophy, leading to the loss of muscle mass and strength, its deficit negatively impacts muscle homeostasis and leads to the occurrence of several pathological phenotypes. A growing number of studies have linked UPS impairment not only to matured muscle fibre degeneration and weakness, but also to muscle stem cells and deficiency in regeneration. Emerging evidence suggests possible links between abnormal UPS regulation and several types of muscle diseases. Therefore, understanding of the role of UPS in skeletal muscle may provide novel therapeutic insights to counteract muscle wasting, and various muscle diseases. In this review, we focussed on the role of proteasomes in s...
AJP: Endocrinology and Metabolism, 2008
Vazeille E, Codran A, Claustre A, Averous J, Listrat A, Béchet D, Taillandier D, Dardevet D, Attaix D, Combaret L. The ubiquitinproteasome and the mitochondria-associated apoptotic pathways are sequentially downregulated during recovery after immobilization-induced muscle atrophy. Immobilization produces morphological, physiological, and biochemical alterations in skeletal muscle leading to muscle atrophy and long periods of recovery. Muscle atrophy during disuse results from an imbalance between protein synthesis and proteolysis but also between apoptosis and regeneration processes. This work aimed to characterize the mechanisms underlying muscle atrophy and recovery following immobilization by studying the regulation of the mitochondria-associated apoptotic and the ubiquitin-proteasome-dependent proteolytic pathways. Animals were subjected to hindlimb immobilization for 4 -8 days (I4 to I8) and allowed to recover after cast removal for 10 -40 days (R10 to R40). Soleus and gastrocnemius muscles atrophied from I4 to I8 to a greater extent than extensor digitorum longus and tibialis anterior muscles. Gastrocnemius muscle atrophy was first stabilized at R10 before being progressively reduced until R40. Polyubiquitinated proteins accumulated from I4, whereas the increased ubiquitination rates and chymotrypsin-like activity of the proteasome were detectable from I6 to I8. Apoptosome and caspase-3 or -9 activities increased at I6 and I8, respectively. The ubiquitinproteasome-dependent pathway was normalized early when muscle stops to atrophy (R10). By contrast, the mitochondria-associated apoptotic pathway was first downregulated below basal levels when muscle started to recover at R15 and completely normalized at R20. Myf 5 protein levels decreased from I4 to I8 and were normalized at R10. Altogether, our results suggest a two-stage process in which the ubiquitin-proteasome pathway is rapidly up-and downregulated when muscle atrophies and recovers, respectively, whereas apoptotic processes may be involved in the late stages of atrophy and recovery.
Molecular and cellular biochemistry, 2001
The activity of ATP, ubiquitin (Ub)-dependent proteases partially purified from skeletal muscle (psoas) from alloxan diabetic rabbits was determined at different periods of insulin deficiency. Two days after alloxan injection, no change was observed in the activity of ATP, Ub-dependent proteases, but this activity increased 3 and 5 days after diabetes induction, attaining 181% of control values on the 5th day. However, after this early rise, the activity of muscle ATP, Ub-dependent proteases decreased, returning to values that did not differ significantly from controls 7 and 10 days after alloxan injection. After 15 days, the activity of these proteases was 57% lower than in muscle from control rabbits. Both the initial increase and the subsequent fall in the activity of the enzymes were prevented by insulin treatment of alloxan diabetic rabbits. The data suggest that Ub-proteasome-dependent proteolysis have an important role in the control of muscle protein degradation and may be r...