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Biomedical subjects

A Sébille

Publications and source records attributed to A Sébille.

14 recordsLinked to original sources
PubMed2000

Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice.

Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the IkappaBalpha/nuclear factor kappaB pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.

Animals↗
PubMed2000

Skeletal muscle regeneration is not impaired in Fgf6 -/- mutant mice.

FGF6 is a member of the fibroblast growth factor family. The Fgf6 gene is almost exclusively expressed in adult and developing skeletal muscle. We have obtained mice deficient in FGF6 by targeting the Fgf6 gene by homologous recombination. We studied regeneration of adult skeletal muscle in Fgf6 -/- mice derived on a standard inbred background. Muscle degeneration was induced by notexin drug or crush injury. The defect in FGF6 did not modify the kinetics of muscle regeneration. We bred Fgf6 -/- mice with mdx dystrophin deficient mice; Fgf6 -/-:mdx and mdx muscles were similar. Our study suggests that FGF6 does not play a role in muscle regeneration, i.e., in satellite cell proliferation and fusion, or that this role is strictly compensated by other factors, possibly other FGFs.

Animals↗
PubMed1998

Mouse muscle regeneration: an in vivo 2D 1H magnetic resonance spectroscopy (MRS) study.

Muscle degeneration and regeneration were studied by 2D 1H magnetic resonance spectroscopy (MRS) and histological examination, in an experimental model of muscle injury using a myotoxic snake venom, notexin. The injured muscles produced a very specific MRS signal, corresponding to a tri-unsaturated fatty acid (linolenic acid-like) signal, from day 2 to day 9 after injury. The combination of MRS with histology showed that this signal was associated with a mechanism occurring during myoblast fusion to form myotubes. 2D 1H MRS is thus a useful non-invasive tool for detecting muscle regeneration in vivo.

Animals↗
PubMed1995

Muscle regeneration following injury can be modified in vivo by immune neutralization of basic fibroblast growth factor, transforming growth factor beta 1 or insulin-like growth factor I.

Previous in vitro studies pointed out the role played by several growth factors (basic fibroblast growth factor or bFGF, transforming growth factor beta-1 or TGF beta 1, insulin-like growth factor-I or IGF-I) on the proliferation, the differentiation and the fusion of myogenic precursor cells. We attempted to modify the muscle regeneration which follows the denervation-devascularization of extensor digitorum longus in mice, by acting on the growth factors which are possibly involved in this process. The injection of neutralizing antibodies against either bFGF or IGF-I into the muscle at the time of lesion reduced the number and diameter of regenerating myofibres, suggesting a delay in proliferation and/or fusion of activated satellite cells. The neutralization of TGF beta 1 led to an increased number of small regenerating myofibres, which would be due to the promoting effects of the remaining growth factors (i.e. bFGF and IGF-I) on myoblast proliferation. These contrasted results strongly suggest that the growth factors regulate in vivo muscle regeneration and would be accessible tools for future therapy of muscular disorders.

Animals↗
PubMed1995

Morphological and functional study of extensor digitorum longus muscle regeneration after iterative crush lesions in mdx mouse.

The regenerative capacity of mdx Extensor Digitorum Longus (EDL) muscle after iterative muscle crush injuries was examined and compared with that of age-matched control C57BL/10 mice. Muscle crush injuries were performed at 8 weeks and repeated at 12 and 16 weeks. Contralateral non-crushed EDLs from mdx and C57BL/10 mice were used as internal controls for histopathology, histoenzymology, morphometry and for the study of the contractile properties. Morphological examinations were performed at 12, 16 and 20 weeks, respectively one month after a single, a second or a third crush. Contractile properties were studied at 12 to 20 weeks. By 20 weeks, no difference in the number of fibres with internal nuclei could be observed between crushed EDL from both strains, and non-crushed mdx EDL; the area and the diameter of crushed EDL from mdx mice were, respectively, 1.5- and 1.2-fold higher than the ones from crushed EDL from C57BL/10 strain. By 20 weeks, diameter distribution of crushed EDL muscles from C57BL/10 mice were shifted towards smaller fibre diameter, whereas in mdx mice, diameter distribution of crushed EDL muscles paralleled that of non-crushed EDL muscles. By 20 weeks, crushed mdx and C57BL/10 EDL muscles produced 77 and 47% of normalized tetanus tension respectively of non-crushed mdx and C57BL/10 EDL muscles. Following crush injury, both 12- and 20-week mdx and C57BL/10 EDL exhibited a slowed time to peak (TTP) and half-relaxation time (H1/2R) of twitch. There was no difference in posttetanic potentiation between the different groups. Crushed EDL of both strains showed an increased resistance to fatigue, compared to the non-crushed controls. The present study provides morphological and functional evidence for the greater recovery of mdx muscle compared to C57BL/10 muscle following iterative crush injury; however, the recovery does not completely prevent the appearance of necrosis/regeneration features.

Animals↗
PubMed1995

The cellular events of injured muscle regeneration depend on the nature of the injury.

The cellular events of muscle degeneration and regeneration and their time course were studied in two experimental models of muscle injury mice; (i) the denervation-devascularization (DD) of the extensor digitorum longus (EDL) muscle, which is an ischaemic lesion; (ii) the injection of notexin (NOT), a snake venom, in the tibialis anterior (TA) muscle, resulting in a toxic lesion. Compared to the ischaemic lesion, the toxic lesion was characterized by a more extensive inflammatory infiltrate and a shortened phase of phagocytosis of the damaged myofibres. This allowed the proliferation and differentiation of muscle precursor cells (mpc) to take place earlier and may be further promoted by growth factors released by inflammatory cells. Compared to DD-EDL, NOT-TA showed also a greater conservation of the basement membranes of the necrotic myofibres, that can support the fusion of mpc into myotubes, and a better microvascularization. The onset of muscle regeneration is tightly related to the events which occur during the phase of degeneration.

Animals↗
PubMed1994

[Muscular reconstruction by myogenic cell graft].

We have developed an experimental model to test the ability of cultured satellite cells to form new muscle fibers when grafted in an irreversibly injured muscle. Association of X-irradiation to autotransplantation reduced extensor digitorum longus muscles of adult rats to a cystic structure formed by a peripheral rim of surviving muscle fibers surrounding a central space devoid of myofibers. Grafting autologous satellite cells, multiplied and labelled in vitro, into this central space gave rise to new myotubes which developed and matured to form fully differentiated myofibers. Mecanophysiological recordings confirmed the improvement of functional parameters particularly a 4 fold increase of twitch and tetanic tensions in grafted muscles. Furthermore, we examined the role of old basal lamina in architectural organisation of the reconstituted muscle by electron microscopy and immunofluorescence using antibodies to laminin, fibronectin, type IV collagen and heparan sulfate proteoglycan. We observed the persistence of immunoreactivity to all components; anti-laminin antibodies for example, evidenced a clear fascicular organization of ghost basal lamina which are progressively repopulated by the grafted cells. We finally investigated in vivo proliferation of the grafted cells by an autoradiographic study of H3-thymidine incorporation in the regenerated fibers and demonstrate that grafted cells proliferate for, at least, 1 week after cell grafting.

Analysis of Variance↗
PubMed1991

[Improvement of muscular re-innervation by using an enriched biological glue in the rat].

The use of biological glue for the repair of nerve lesions offers the possibility of acting on axonal regeneration by means of trophic substances included in the glue. A comparative study conducted in the sciatic nerve of the rat shows that incorporation of the liquid exuded by sectioned nerve extremities into the glue to repair a section of the sciatic nerve trunk of other animals significantly increases the muscular tension of the force jerk and the of tetanic contraction of the reinnervated extensor digitorum longus 21 and 28 days after repair. It therefore appears possible to influence the regeneration or the maturation of the regenerating axons by local application of exogenous substances.

Animals↗
PubMedDate not supplied

The basic fibroblast growth factor-saporin mitotoxin impairs in vivo skeletal regeneration following injury.

Basic fibroblast growth factor (bFGF) is known to promote the proliferation of myogenic cells in vitro and has been detected in regenerating muscle in vivo. We attempted to modify in vivo post-injury muscle regeneration by acting through the potential involvement of bFGF and the presence of bFGF receptors on regenerating myogenic cells. For this purpose, bFGF conjugated to saporin, a potent mitotoxin, was injected in denervated-devascularized extensor digitorum longus of mice. Cytotoxicity occurred in the regeneration process, as shown by the significantly reduced number and the smaller diameter of the regenerating myotubes, probably determined by the binding of the toxic conjugate to bFGF receptors of myogenic cells. This study describes a suitable in vivo model to develop this specifically-mediated cytotoxicity, which offers new perspectives for acting on muscle regeneration disorders.

Animals↗
PubMedDate not supplied

Functional recovery induced by satellite cell grafts in irreversibly injured muscles.

Grafting autologous cultured satellite cells in irreversibly injured rat extensor digitorum longus EDL muscle leads to myofiber regeneration at the grafting site. In this study, we investigated whether cell grafts induced functional improvement and correlated mechanophysiological findings with histological observations. In cell grafted muscles, the number of myofibers did not differ significantly between 2 wk and 3 mo, whereas no regenerating myofibers were observed in ungrafted controls. During this period, the total number of myofibers in the cell grafted muscles represented 48.2-51.9% of that in normal muscles. The mean diameter of regenerated myofibers increased with time, reaching a maximum (32 microns) at the second mo and remained smaller than that of normal myofibers (47 microns). Muscle function was measured by mechanophysiological recordings of muscle response to supramaximal electrical stimulation of the nerve in situ. Cell grafted muscles exhibited a progressive improvement of all contractile parameters. After 3 mo, a 4-fold increase in absolute values of twitch and tetanic tension outputs was measured in cell grafted muscles when compared to ungrafted controls. However, these parameters remained much lower than in normal muscles (23.4% and 22.3% of control, respectively). This study showed that myogenic cell grafts replace degenerated myofibers and form functional myofibers. Functional improvement observed, between 2 wk and 3 mo after cell grafting, correlated with the development, differentiation, and maturation of the regenerated myofibers rather than with an increase in the number of regenerated myofibers.

Animals↗