Biomedical subjects

A Meeson

Publications and source records attributed to A Meeson.

6 recordsLinked to original sources

PubMed2001

Functional and molecular adaptations in skeletal muscle of myoglobin-mutant mice.

Myoglobin is a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers and facilitates oxygen delivery during periods of high metabolic demand. Myoglobin content in skeletal muscle increases in response to hypoxic conditions. However, we previously reported that myoglobin-null mice are viable and fertile. In the present study, we define important functional, cellular, and molecular compensatory adaptations in the absence of myoglobin. Mice without myoglobin manifest adaptations in skeletal muscle that include a fiber type transition (type I to type II in the soleus muscle), increased expression of the hypoxia-inducible transcription factors hypoxia-inducible factor (HIF)-1alpha and HIF-2 (endothelial PAS domain protein), stress proteins such as heat shock protein 27, and the angiogenic growth factor vascular endothelial growth factor (soleus muscle), as well as increased nitric oxide metabolism (extensor digitorum longus). The resulting changes in angiogenesis, nitric oxide metabolism, and vasomotor regulation are likely to account for preserved exercise capacity of animals lacking myoglobin. These results demonstrate that mammalian organisms are capable of a broad spectrum of adaptive responses that can compensate for a potentially serious defect in cellular oxygen transport.

Adaptation, Physiological↗

PubMed2000

Myogenic stem cell function is impaired in mice lacking the forkhead/winged helix protein MNF.

Myocyte nuclear factor (MNF) is a winged helix transcription factor that is expressed selectively in myogenic stem cells (satellite cells) of adult animals. Using a gene knockout strategy to generate a functional null allele at the Mnf locus, we observed that mice lacking MNF are viable, but severely runted. Skeletal muscles of Mnf-/- animals are atrophic, and satellite cell function is impaired. Muscle regeneration after injury is delayed and incomplete, and the normal timing of expression of cell cycle regulators and myogenic determination genes is dysregulated. Mnf mutant mice were intercrossed with mdx mice that lack dystrophin and exhibit only a subtle myopathic phenotype. In contrast, mdx mice that also lack MNF die in the first few weeks of life with a severe myopathy. Haploinsufficiency at the Mnf locus (Mnf+/-) also exacerbates the mdx phenotype to more closely resemble Duchenne's muscular dystrophy in humans. We conclude that MNF acts to regulate genes that coordinate the proliferation and differentiation of myogenic stem cells after muscle injury. Animals deficient in MNF may prove useful for evaluation of potential therapeutic interventions to promote muscle regeneration for patients having Duchenne's muscular dystrophy.

Animals↗

PubMed2000

Life without myoglobin.

Hemoproteins are widely distributed among prokaryotes, unicellular eukaryotes, plants and animals [1]. Myoglobin, a cytoplasmic hemoprotein that is restricted to cardiomyocytes and oxidative skeletal myofibers in vertebrates, has been proposed to facilitate oxygen transport to the mitochondria [1-3]. This cytoplasmic hemoprotein was the first protein to be subjected to definitive structural analysis and has been a subject of long-standing and ongoing interest to biologists [1-3]. Recently, we utilized gene disruption technology to generate mice that are viable and fertile despite a complete absence of myoglobin [4]. This unexpected result led us to reexamine existing paradigms regarding the function of myoglobin in striated muscle.

Animals↗

PubMed1996

Comparison of a Chemically Mediated and an Immunologically Mediated Demyelinating Lesion Model

The production of two animal models for the central nervous system degenerative condition multiple sclerosis is described in detail. The first is a chemically mediated noninflammatory demyelinating lesion of the brain stem induced by the injection of a trypanocidal DNA binding dye, ethidium bromide, into the cerebellomedullary cistern. The injection does not involve any physical damage to the blood-brain barrier or the CSF-brain barrier and is simple to perform. The second lesion model is an immunologically mediated demyelinating condition involving the injection of a T-cell line specific for myelin basic protein, followed by injection of a monoclonal antibody against the myelin surface protein, myelin/oligodendrocyte glycoprotein. We describe the production of the antigen-specific T-cell line in detail. This model is characterized by widespread inflammatory infiltrates accompanied by areas of demyelination. Both of these models are produced in the Lewis rat, allowing the direct comparison of mechanisms involved in demyelination and repair in the presence or absence of invading inflammatory cells. Despite the very different etiologies of the two lesion models, they are both acute and result in efficient remyelination.

Journal Article↗

PubMed1996

A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis.

Previous analyses of developmentally programmed capillary regression suggested two distinct causes of vascular endothelial cell (VEC) death. The first appeared to be macrophage-dependent (Lang, R. A. and Bishop, M. J. (1993) Cell 74, 453-462) while the second was proposed to result from cessation of blood flow (Lang, R. A., Lustig, M., Francois, F., Sellinger, M. and Plesken, H. (1994). Development 120, 3395-3403). Combined, these analyses suggested a model in which initial, macrophage-mediated endothelial cell apoptosis blocked blood flow within a capillary segment and, as a consequence, caused apoptosis of all remaining cells in the affected segment. In the current study, we have tested this model using a new method that combines vital and histological analyses as a means of determining the fate of whole capillary segments and individual cells in vivo. This technique revealed that one of the first events in regression was the apoptosis of a single VEC in otherwise normal, flowing capillary segments (initiating apoptosis). These isolated, dying VECs projected into and restricted the capillary lumen, imposing either a temporary or permanent block to blood flow. Following cessation of flow, synchronous apoptosis of VECs occurred (secondary apoptosis). In addition, a quantitative analysis revealed a reciprocal relationship between plasma flow and VEC apoptosis. These observations are consistent with a model for capillary regression in which macrophages induce apoptosis in a limited number of VECs and, as a consequence of a block to blood flow, also cause apoptosis in those remaining.

Animals↗

PubMedDate not supplied

Immunocytochemical characterization of primary glial cell cultures from normal adult human brain.

Primary cultures were established from autopsy or biopsy samples of normal adult human brain and characterized by immunocytochemical techniques. Initially, macrophages were the predominant cell type adhering to the substratum, but as their number fell that of glial cells increased. Oligodendrocytes comprised 30% of the glial population in white matter cultures, and their perikarya and elongated processes were immunostained with antibodies directed against galactocerebroside and four myelin proteins. In white and grey matter cultures, process-bearing astrocytes and small numbers of polygonal astrocytes were stained with antibodies against glial fibrillary acidic protein and glutamine synthetase. Fibroblasts started to appear at 3 weeks and proliferated to form a monolayer beneath glial cells by 5 weeks. Glia began to die in the 6th week. These primary cell cultures of white or grey matter can be used to study the properties of glial cells from normal or pathological adult human brain.

Adolescent↗