Gene regulation and morphogenesis

Regulation of skeletal muscle mass and function from development to ageing

Dra Cristina Vicente García
Researcher associated to Dr Jaime Carvajal

Summary
Five relevant publications
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Summary

The myogenic regulatory factors (MRFs) Myf5, Mrf4, MyoD and MyoG are transcription factors that control the determination, specification and differentiation of skeletal muscle during development. Interestingly, Mrf4 is the only family member expressed after birth in muscle fibers, suggesting it plays a role in postnatal muscle growth and homeostasis. Indeed, the inactivation of this gene in adult rat muscle causes increased protein synthesis leading to fiber hypertrophy, while preventing denervation-induced atrophy. This is accompanied by the necessary changes in energy metabolism to maintain appropriate muscle function. Thus, Mrf4 or its downstream target network could be used as potential targets for the treatment of conditions leading to muscle mass loss, including muscle-wasting disorders, atrophy by disuse and age-related sarcopenia.

To explore this possibility, in our lab we aim at determining Mrf4 specific functions, which, surprisingly, remain unknown to date in spite of the three knock-out models available for over two decades. The reason is that these models show a disparity in phenotype that ranges from complete viability to lethality at birth; skeletal defects appear in all cases.

By studying the long-range interactions established in the locus by means of the 4C technique, we can confirm that the neighboring Myf5 gene, only 8.7 kb apart, is affected to various extents in these models, making them behave phenotypically as compound Mrf4/Myf5 mutants and thus obscuring Mrf4 specific functions. Therefore, using the CRISPR/Cas9 technology we have created novel alleles that do not affect Myf5 expression, in order to start unravelling the full developmental and adult functions of Mrf4, as well as during ageing. Our studies indicate that the lack of Mrf4 is associated with a wide range of phenotypes, many of which are muscle type-, age- and/or sex-specific. Hypertrophy, hypoplasia, increased strength, or mitochondrial respiration defects are some of the phenotypes that arise in the absence of Mrf4.

Strikingly, even if this gene is only expressed in skeletal muscle, its deficiency leads to alterations in other organs as well, such as bones, the adipose tissue, or the heart. Thus, we hypothesize that Mrf4 might be involved in the crosstalk between muscle and other tissues, especially during development.

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