University of Missouri-Kansas City, Spencer Building, 5009 Rockhill Rd., Kansas City, MO 64110
OUR RESEARCH (FOR NON-SCIENTISTS)
Why study muscles?
What is alternative splicing?
What is alternative splicing?
We study how muscles develop and what goes wrong in muscle disease.
What is alternative splicing?
What is alternative splicing?
What is alternative splicing?
We study how RNA regulation and alternative splicing influence muscle function.
Flies have muscles!?
What is alternative splicing?
Flies have muscles!?
We use fruit flies, Drosophila melanogaster, as a model organism.
Dr. Spletter's 2018
TEDxTUM talk
Curious? Motivated to learn more? Check out this animated and easy-to-understand presentation on YouTube.
Muscle Biology
Why do we study muscles?
Muscles are essential for life, as they allow our bodies to move. We use muscles for conscious movements, such as writing and walking, as well as unconscious movements, such as beating of the heart, the digestive action of the stomach, or breathing. We have hundreds of muscles in our bodies that are used for different types of movements. Loss of muscle function in diseases from cancer to heart disease can be catastrophic, leading to poor quality of life and even death. Unfortunately, scientists still only partially understand how different muscles form during development and what goes wrong in patients with muscle diseases. Our research in the Spletter lab aims to address this gap in the understanding of basic principles of muscle development and disease.
Muscles are able to power movement because they contract, meaning they are able to shorten and lengthen. This contraction ability is powered by mini-motors called sarcomeres. Muscles are built of many fibrils containing thousands of sarcomeres, and when all of the motors work together, they allow the muscle to contract. Sarcomeres are built of two major components: the protein actin, which forms long, track-like filaments, and the protein myosin, which is a motor that walks up and down the actin. By regulating how fast the myosin motor moves and how long it can move along the actin track, muscles can fine-tune how often and how strongly they contract. This is the basic principle that allows the heart to pump blood, while muscles in the legs contract with different dynamics to permit walking. Many diseases change the structure or the contractile ability of sarcomeres, and we study the molecular and genetic changes that lead to a loss of muscle function or a change in muscle performance.
Word cloud of terms generated from abstracts of our published papers, highlighting a focus on muscle
RNA biology
What is RNA and alternative splicing?
Our genes are contained in the DNA and used to make proteins that build the cells in our bodies. RNA is the go-between: genes in the DNA are copied in the form of RNA, and this RNA blueprint is then read to synthesize the corresponding protein. RNA biology is the field that studies everything RNA: how RNA's are made, how they move through the cell, how they are modified, and how they are turned into protein. RNA-binding proteins supervise this process, as they have the ability to recognize and direct an RNA molecule along its journey to becoming a protein. The Spletter lab is interested in RNA-binding proteins because multiple muscle diseases, in particular several forms of heart disease as well as Myotonic Dystrophy Type I (DM1), are caused by loss or abnormal activity of RNA-binding proteins.
In the DNA, most genes are broken-up into multiple segments, called exons, that have to be glued back together by a process called splicing after they are copied into RNA. Many cells intentionally glue the exons back together in multiple patterns, allowing one gene to generate the RNA blueprints for multiple proteins. Multiple proteins produced from the same gene are called isoforms. This process is called alternative splicing and is very common: more than 60% of genes in flies and 90% of genes in humans can produce multiple proteins. The two tissues with the highest levels of alternative splicing are muscles and the brain.
Alternative splicing allows muscles to modify their sarcomeres to adapt to physical demand. For example, the heart needs to be very stiff to properly pump blood, while muscles in the legs are much more flexible. Alternative splicing of sarcomere proteins generates multiple versions of the same protein that for example can be more or less stiff or interact more strongly or weakly with other proteins, ultimately helping define specific contractile properties for different muscle types. In muscle diseases like heart disease and DM1, misregulation or loss of RNA-binding proteins causes muscles to produce the wrong protein isoforms, for example a version of the protein normally found in leg muscle can now be found in the heart. Patients with these disorders experience a loss of muscle and impaired muscle function. The goal of our research is to understand how regulators of alternative splicing work, and what goes wrong in muscle disease. A better understanding of how muscles develop normally and what is disrupted in disease will aid in developing new treatments for these debilitating disorders.
We use molecular biology techniques such as PCR, electrophoresis, and RNA-seq to study RNA splicing.
Drosophila biology
Why would you study a fruit fly?
Most people know Drosophila as those pesky fruit flies buzzing around the bananas. Scientists know Drosophila as a model organism: an animal that is well characterized, that has a lot of established tools to use for experiments, and where we know all of the genes contained in the DNA. We can use flies as a model to investigate basic principles of biology that also apply to humans.
Just like other animals, flies have muscles that let them eat, walk, and fly. Drosophila muscles are built of the same sarcomeres, contain many of the same proteins, and contract by the same mechanism that powers human muscles. The picture on the right shows the muscles that power flight, which are similar to human heart or skeletal muscle. Many of the same genes that control human muscle development also control muscle development in flies, so we can use fly muscle as a model to understand how our own muscles work.
Flies have several advantages over humans that make them a particularly useful model to understand how cells, tissues, and organs work. First, flies have a fast life cycle. It takes humans ~20-25 years to reach full maturity, but flies reach full maturity in only 10 days! Second, flies have hundreds of progeny, so we can examine hundreds of individuals in a short period of time and have statistical confidence in our results. Third, we can use genetic engineering approaches in flies to modify the DNA and test the effect of disease causing mutations, as well as to test how well drugs or new therapies work to treat disease. Our findings in flies can be translated to understand how human bodies work and to advance biomedical science.
Drosophila muscles. The indirect flight muscles, in green, fill most of the thorax of a fly.