Skeletal muscle mass control by microRNA-29c manipulation: a molecular intervention approach

Abstract

Skeletal muscle dysfunction results in inadequate control of homeostasis and particularly a significant skeletal muscle loss (sarcopenia) has a substantial negative impact in the senile fragility syndrome onset in aging. This syndrome is characterized by an increased mortality due an individual's lower ability to maintain vital functions and typical immunological response. Furthermore, we can observe marked skeletal muscle loss after joint injuries, for instance, anterior cruciate ligament rupture. After the ligament injury, a severe skeletal muscle wasting of the stabilizing musculature leads to a lengthy rehabilitation process, even after the ligament reconstruction. Both examples endorse the need to developing therapeutics that enable the maintenance of muscle mass and function, which is the context of this proposal. In this sense, we demonstrated previously that miR-29c hyperexpression induced a 40% increase in skeletal muscle mass and force, regardless of the mechanical load. Also, preliminary data (shown in this proposal) indicates that this microRNA may also have an anti-atrophic action. Herein, we will address miR-29c ergogenic effects upon skeletal muscle in atrophy (denervation, glucocorticoids, and cancer cachexia) and hypertrophy models (electrical stimulation). Next, functional (muscle strength), morphometric (muscle mass, cross-sectional area of different types of muscle fibers), and molecular (gene expression of pathways linked to atrophy and hypertrophy) aspects of the skeletal muscle will be evaluated. In addition, we will carry out a prospective experiment to identify miR-29c responsive-mRNAs, microRNAs, and long non-coding RNAs regulated by these different conditions. Together, our results and literature content support miR-29c therapeutic potential. Furthermore, understanding its possible interaction with the mechanical stress imposed by muscle contraction may open the possibility of future approaches involving clinical conditions in which it is desired to contain the loss or optimize muscle mass gain. (AU)