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miR-1: an ancient molecule controls muscle physiology

15 Oct 2021
Explanatory science sketch - see video below.

Muscle cells are particularly sensitive to disruptions in their metabolism. Severe muscle diseases may be caused by mutations that spare other tissues. Scientists at the Research Institute of Molecular Pathology (IMP) in Vienna have uncovered the mechanism behind a muscle-cell vulnerability mediated by the microRNA miR-1. The results of their study have been published in the current issue of the journal Science Advances.

A defining feature of animals is their ability to move in order to eat, mate or avoid danger. Strong and healthy muscles are essential for generating force and regulating energy metabolism. To fulfill these functions, muscle cells have evolved unique structural and molecular specialisations. A complex contractile apparatus creates movement and specific metabolic adaptations support the high energy demands.

These specialisations come at a cost, making muscle cells selectively vulnerable to genetic or environmental perturbations that do not affect other cell types. Two interacting organelles that are of critical importance to muscle function are particularly sensitive: mitochondria, which act as the “power houses” of the cell, and lysosomes, which perform as its “recycling center”. Mutations that affect these organelles are among the most common causes of muscle diseases, or myopathies.

Scientists have been intrigued by the fact that such adverse mutations may occur in genes that are active throughout the body, yet only have severe consequences in muscle. To address the mechanism by which mutations cause myopathies while sparing other tissues, researchers at the IMP Vienna have carried out extensive studies using the microRNA miR1. MicroRNAs are small, single-stranded RNA molecules that regulate gene expression on a post-transcriptional level by silencing messenger RNAs. Like other microRNAs, miR-1 is a cell-specific repressor and can therefore provide key insights into which processes need to be selectively controlled in a specialized cell, such as a muscle cell.

Among all microRNAs, miR-1 is unique in that its sequence and expression pattern have remained almost unchanged over millions of years of evolution. It is specifically expressed in muscle and is essential for cardiac and skeletal muscle development and function across the animal kingdom. But despite its vital role, its mechanism of action is still not understood.

In experiments with nematode worms and flies, former Vienna BioCenter PhD Student Paula Gutiérrez-Pérez, together with researchers from the lab of Luisa Cochella found that the critical role of miR-1 is to control the mitochondrial-lysosomal axis. Its most significant target is the vacuolar ATPase (V-ATPase), an enzyme which acidifies organelles by pumping protons across membranes. This activity is essential for lysosomes to function, among other vital roles in the cell’s metabolism. Strikingly, although miR-1 acts as a repressor of individual components of the V-ATPase, its absence does not cause V-ATPase-activity to go up but rather disrupts it.

“Our work indicates that miR-1 repression is necessary for the correct assembly and function of the intricate V-ATPase complex in muscle cells”, says Luisa Cochella, a former Group Leader at the IMP who recently joined Johns Hopkins School of Medicine as Assistant Professor. “The absence of this regulation has dramatic consequences for muscle cells and provides insight for understanding muscle physiology in disease states.”     

Apart from multiple subunits of V-ATPase, the IMP researchers also identified another target of miR-1, the mitochondrial protein BNIP3. Together, the findings uncover an ancient regulon, a group of genes that are controlled as a unit, as first author Paula Gutiérrez-Pérez explains: “Our work revealed a deeply conserved miR-1 dependent regulon that is critical for muscle physiology and supports a novel role for microRNAs in the assembly of protein complexes.” The authors are confident that their findings will provide advances to multiple fields of research, including miRNA-mediated regulation, protein complex assembly and muscle cell physiology.

Original Publication

Paula Gutiérrez-Pérez, Emilio M. Santillán, Thomas Lendl, Jingkui Wang, Anna Schrempf, Thomas L. Steinacker, Mila Asparuhova, Marlene Brandstetter, David Haselbach and Luisa Cochella. miR-1 sustains muscle physiology by controlling V-ATPase 1 complex assembly. Science Advances online, Friday, 15 October 2021.