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Skeletal myofibers are syncytia made from the fusion of dozens or hundreds of mononuclear progenitor cells. Along myogenesis, the arriving nuclei from the progenitor cells have a long journey before being positioned at the periphery of a mature myofiber. Once at the periphery, nuclei are regularly spaced and each nucleus is transcriptionally responsible for its surrounding proportion of cytoplasm, known as the myonuclear domain. Disruption of these domains can be observed in various myopathies, suggesting their importance for skeletal muscle functionality. However, little is known about mechanisms regulating the myonuclear domain stability and organization. Here we take the example of MACF1, a microtubule-associated protein, as an essential actor in myonuclear domain organization, to highlight the potential role of microtubules and their associated proteome network for the stability of these domains and hence for proper myofiber functionality., (© 2024 médecine/sciences – Inserm.)

Several clinical trials on cell therapy have recently been conducted in the treatment of urinary incontinence. The cell preparation procedures and the inclusion criteria were different for each study. The feasibility of this technology, however, seems acquired. The indications for treatment and the long-term effects have yet to be specified. Cell therapy for urinary incontinence is only conceivable within the context of a clinical trial at this time. We encourage all investigator-urologists involved in a clinical trial on cell therapy to make themselves known on the website http://clinicaltrials.gov so as to inform the community and encourage the technique's development., ((c) 2010 Elsevier Masson SAS. All rights reserved.)

Deciphering the mechanisms underlying skeletal muscle differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20-25 base pairs) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms and in mammals. miRNAs modulate gene expression by affecting mRNA translation or stability. In lower organisms, miRNAs are essential for cell differentiation during development; some miRNAs are involved in maintenance of the differentiated state. We have shown that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype - even when they are not expressed in the corresponding fully differentiated tissue.

Skeletal muscle is made of multinucleated postmitotic fibers which are the agents of contraction. These fibers arise from mononuclear precursor cells which fuse after having migrated from the somites to the site of myogenesis. The cascade of events which result in muscle differentiation is well known nowadays (Sabourin & Rudnicki, 2000). Some precursor cells present in adults muscle are termed satellite cells (Mauro, 1961), because of their location between the plasma membrane and the extracellular matrix of muscle fibers. Since they have a role in muscle growth and regeneration, these cells were the first candidates for treating muscle dystrophies. Despite a large corpus of positive experimental data about transplantation of these cells, no hard clinical result has been obtained to date, However these investigations have led to fruitful thinking about heterogeneity of muscle cell precursors and the possible ways to use them for therapy.

The authors report the first intramyocardial transplantation of autologous skeletal myoblasts in a patient with severe ischaemic cardiac failure. The encouraging result after eight months' follow-up underlines the potential of this new approach.

Sarcopenia associated with the normal aging process is often combined with the detrimental effects of a sedentary lifestyle in older adults, leading to a significant reduction in reserve capacity of the neuromuscular system. A clear example of the aging effect is the pattern of reduction in muscle strength after the sixth decade for both isometric and concentric contractions. However, older adults are relatively stronger for movements in which muscles lengthen, due to the inherent advantage of eccentric contractions, plus their stiffer muscle structures and prolonged myosin cross-bridge cycles. Also, the capacity for physiological adaptations in the motor pathways remains into very old age when an appropriate exercise stimulus is given, and older adults can obtain adaptations in both enhanced neural control of motor units and increased protein synthesis leading to moderate muscle hypertrophy. Since periods of sedentary lifestyle or bed rest due to illness can have severe detraining consequences on the neuromuscular function of an older person, long-term prevention strategies are advocated to avoid excessive physical impairments and activity restrictions in this age group.

The clinical trials of myoblast transplantation in Duchenne Muscular Dystrophy (DMD) patients produced disappointing results. The main problems responsible for these poor results have since then been identified and partially resolved. One of them was related to the use of an inadequate immunosuppression and, since then, immunosuppression with FK506 has permitted successful myoblast transplantation not only in mice but also in monkeys. The requirement for a sustained immunosuppression may be eventually avoided by developing a state of tolerance to the allogeneic cells or by autologous transplantation of genetically corrected myoblasts or stem cells. The rapid death of 75-80% of the injected myoblasts during the first five days has also contributed to the limited success of the early trials. This death was due to an inflammatory reaction and has been compensated in animal experiments by the injection of a larger number of cells (30 millions per cc). Finally, the myoblasts migrated only 0.5 mm away from their site of injection. This problem is currently compensated in animal experiments by injecting the myoblasts at every mm. The number of injections required may eventually be reduced by transfecting myoblasts with one or several metalloproteinase genes. The very good results obtained during the last two years in primates permit us to undertake a new phase I clinical trial to verify that myoblast transplantation can lead to the formation of muscle fibers expressing normal dystrophin in muscles of DMD patients.

Despite medical therapeutic advances, congestive heart failure (CHF), which is the common ultimate consequence of many primary cardiovascular diseases, remains a major and growing public health problem. Although orthotopic heart transplantation is the gold standard, there is now growing evidence that one therapeutic option could be cellular cardiomyoplasty. Autologous adult skeletal myoblast transplantation seems to be the most clinically relevant, compared with other cell types, in that it avoids immunosuppression therapy, availability and ethical issues. Previous experimental studies have documented the efficacy of myoblast transplantation in improving function of infarcted myocardium. Although the mechanisms involved in this improvement are not elucidated, it has been demonstrated convincingly enough to consider ripping to clinical trials.

Muscle cells, including smooth muscle cells, cardiac muscle fibers and skeletal muscle fibers, are specialized for generation of movement and force in a specific direction. Smooth muscle cells are mononucleate cells, isolated or grouped in layers in various tissues, or rarely forming individualized muscles. Smooth muscle cell contraction is slow and depends on the autonomic nervous system. Cardiac muscle cells are mononucleate striated cells, with fast, rhythmic, spontaneous contractions. Skeletal muscle fibers are multinucleate cells at the origin of voluntary movements. According to morphological and functional criteria, skeletal muscle fibers are classified as type I fibers (slow-twitch oxidative), type IIA fibers (fast-twitch oxidative glycolytic) or type IIB fibers (fast-twitch glycolytic).

Many reasons, in 1996, may incite orthopaedic surgeons to take an interest in cell culture. Firstly, cell culture bring informations on bone cell physiology, and the physiological properties of the skeletal cells are involved in the success of the orthopaedic surgeon's act. Secondly, in orthopaedics field's literature, more and more articles using cell culture techniques are published and surgeons need some basic knowledges to understand these results. Then, in the first part of this work, we detail the essential rudiments; vocabulary, cell culture methods, and cell physiology notions. In the second part of this work, we resume the progress realized these last years with cells cultured from the skeleton. Using these informations, surgeons will be able to appreciate the potential uses of cell cultures for diagnosis, biomaterial evaluation and for the development of new therapies.

RGTA11 is a chemically substituted dextran that mimics some of the properties of heparin or heparan sulphates towards heparin binding growth factors as well as inhibits some heparin binding proteases. In vivo RGTA11 has been shown to enhance muscle regeneration after crush. We now present evidence that RGTA11 can alos favour reinnervation of fast (EDL) as well as slow (soleus) crushed muscles. Both types of muscles were injected with RGTA11 after crushing and nerve cutting. In EDL muscles, after 16 days, motor end plates were more rapidly reformed and choline acetyl-transferase activity was 2 fold higher than in controls. In soleus muscles, after 16 days, motor end plates were reformed at normal size while controls were on average 30% smaller, the 16S form of acetyl-cholinesterase and choline acetyl-transferase activity were twice those of non injected regenerating controls. In conclusion, RGTA11 favours axonal growth and synaptic differentiation, allowing a more rapid reinnervation and maturation of the regenerated fibers. RGTA may present a new family of drugs against neuromuscular degenerescence.

Dextran derivatives were obtained by controlled successive substitutions of carboxymethyl, carbomethyl-benzylamide and carboxymethyl-benzylamide sulfonate groups on glucose residues. Among these derivatives, RGT11 was selected since it mimicked some properties of heparin or heparan sulfate to stabilise and protect heparin binding growth factors such as FGFs and TGF-beta. Furthermore RGT11 inhibited plasmine and leukocyte elastase. In previous works, we have explained the healing effects of RGT obtained in skin or bone repair models by these protecting and inhibiting properties. We now present the results obtained after a single injection of RGT11 in a regenerating crushed extensor digitorum longus (EDL) muscle. After 8 days, RGT11 injected muscles contained 10 times the number of fibers than controlled injected muscles. Fibers were organized in bundles of normal size. Histological analysis indicated that regeneration was comparable to that observed after 3 weeks without RGT. Hence in vivo, RGT11 could act by protecting the heparin binding growth factors involved in the natural process of muscle regeneration and therefore favour their actions. This family of polymers should offer a new pharmaceutical potential for treating muscle atrophy and destruction and is worth studying further.

Skeletal muscle sarcolemmal vesicles from control (C) and hindlimb suspended (S) rats were used to investigate the effect of unweighting on the lactate transporter activity. Sarcolemmal preparations were not different between the two groups. The efficiency of 4 weeks of hindlimb suspension was confirmed by a 40% decrease of citrate synthetase activity and a shift towards faster myosin isoforms in soleus muscle. The time course of 1 mM lactate uptake showed that the equilibrium was reached faster in group C (20 s) than in group S (40 s). The initial rate of 1 mM of lactate uptake decreased significantly (p < 0.05) after 4 weeks of hindlimb suspension. The initial rate of 50 mM lactate uptake did not differ significantly between the two groups. We conclude that 4 weeks of unweighting decreases significantly the skeletal muscle sarcolemmal lactate transport activity in rats. This result suggests that the level of physical activity probably plays a role on lactate transport regulation in muscle.