Charge, Sophie B. P., and Michael A. Rudnicki. Cellular and Molecular Regulation of Muscle Regeneration. Physiol Rev 84: 209–238, 2004; 10.1152/physrev.00019.2003.—Under normal circumstances, mamma...

Cellular and Molecular Regulation of Muscle Regeneration

Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process invol...

Satellite Cells and the Muscle Stem Cell Niche

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Function and genetics of dystrophin and dystrophin-related proteins in muscle

Metazoans contain multiple types of muscle cells that share several common properties, including contractility, excitability, and expression of overlapping sets of muscle structural genes that mediate these functions. Recent biochemical and genetic studies have demonstrated that members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors play multiple roles in muscle cells to control myogenesis and morphogenesis. Like other MADS-box proteins, MEF2 proteins act combinatorially through protein-protein interactions with other transcription factors to control specific sets of target genes. Genetic studies in Drosophila have also begun to reveal the upstream elements of myogenic regulatory hierarchies that control MEF2 expression during development of skeletal, cardiac, and visceral muscle lineages. Paradoxically, MEF2 factors also regulate cell proliferation by functioning as endpoints for a variety of growth factor-regulated intracellular signaling pathways that are antagonistic to muscle differentiation. We discuss the diverse functions of this family of transcription factors, the ways in which they are regulated, and their mechanisms of action.

Transcriptional control of muscle development by myocyte enhancer factor-2 (mef2) proteins

Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68(+) M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-alpha and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163(+)/CD206(+) M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor(+)/CD206(+) cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage.

https://www.physiology.org/doi/pdf/10.1152/ajpregu.00735.2009

Regulatory interactions between muscle and the immune system during muscle regeneration

The differential expression of genes triggering myogenesis might cause or reflect differences among myoblasts. Little is known about the presence of MyoD1 and myogenin during the process of regeneration. We therefore examined the expression of MyoD1 and myogenin in muscle regeneration after grafting. Immunostaining of regenerating skeletal muscle of the mouse revealed the presence of both MyoD1 and myogenin. In mononucleated cells the proteins were not detected until shortly before fusion into myotubes. They persisted in the nuclei of regenerated muscle fibers for at least 2 weeks. MyoD1 and myogenin were not detected in nonregenerating control muscle.

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/aja.1001930106

MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse

M-twist is an inhibitor of muscle differentiation.

The murine homologue of the Drosophila twist gene has been shown to be essential for head mesenchyme formation and to act as an inhibitor of muscle differentiation. This paper presents a detailed analysis of M-twist expression patterns from day 7 post coitum (p.c.) to day 18 p.c., indicating a more general function of the M-twist gene. At day 7 p.c., M-twist is expressed in the mesoderm outside the primitive streak. Later M-twist message is predominantly found in the somites, the head mesenchyme, the branchial arches, the limbs, and in the mesenchyme underneath the epidermis. Beginning at day 8 p.c., M-twist is mainly expressed in undifferentiated cells committed to muscle and cartilage development: this expression is consistent with a suggested role of M-twist in inhibiting overt muscle and cartilage differentiation. However, during organogenesis, M-twist is expressed in several areas of mesenchyme-epithelia interactions, suggesting additional tissue specific functions.

Expression of M-twist during postimplantation development of the mouse.

Establishment of a gene-trap sequence tag library to generate mutant mice from embryonic stem cells

Establishment of a gene-trap sequence tag library to generate mutant mice from embryonic stem cells.

A major challenge of the postgenomic era is the functional characterization of every single gene within the mammalian genome. In an effort to address this challenge, we assembled a collection of mutations in mouse embryonic stem (ES) cells, which is the largest publicly accessible collection of such mutations to date. Using four different gene-trap vectors, we generated 5,142 sequences adjacent to the gene-trap integration sites (gene-trap sequence tags; http://genetrap.de) from >11,000 ES cell clones. Although most of the gene-trap vector insertions occurred randomly throughout the genome, we found both vector-independent and vector-specific integration "hot spots." Because >50% of the hot spots were vector-specific, we conclude that the most effective way to saturate the mouse genome with gene-trap insertions is by using a combination of gene-trap vectors. When a random sample of gene-trap integrations was passaged to the germ line, 59% (17 of 29) produced an observable phenotype in transgenic mice, a frequency similar to that achieved by conventional gene targeting. Thus, gene trapping allows a large-scale and cost-effective production of ES cell clones with mutations distributed throughout the genome, a resource likely to accelerate genome annotation and the in vivo modeling of human disease.

https://www.pnas.org/content/pnas/100/17/9918.full.pdf

Ernst-Martin Füchtbauer

Papers

MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse

M-twist is an inhibitor of muscle differentiation.

Expression of M-twist during postimplantation development of the mouse.

Establishment of a gene-trap sequence tag library to generate mutant mice from embryonic stem cells.

A large-scale, gene-driven mutagenesis approach for the functional analysis of the mouse genome