Space-induced muscle atrophy can threaten astronauts’ performance during extended space missions, and Dr. Parker B. Antin is looking at the biomedical causes of this problem. Dr. Antin is exploring ways to reduce muscle atrophy by inhibiting the activity of calpain, an enzyme thought to degrade protein molecules in muscle. Information gained will broaden understanding of muscle growth and may lead to approaches for alleviating muscle atrophy in space and on Earth.
Overview
Calpains in Simulated Microgravity-Induced Muscle Atrophy
Principal Investigator:
Parker B. Antin, Ph.D.
Organization:
University of Arizona
Technical Summary
The overall goal of this project is to test the hypothesis that inhibition of calpain activity in skeletal muscles can reduce myofibril degradation and muscle atrophy. Muscle wasting is an important impediment to extended space travel, and studies have shown that muscle size is regulated by the balance between myofibrillar protein synthesis and degradation.
Calpain is the major calcium activated protease in animal cells and plays a primary role in regulating the rate of muscle protein accumulation. Considerable evidence suggests that increasing the levels of calpastatin, a protein inhibitor of calpains, enhances muscle protein accumulation. Inhibition of calpain activity, either by increasing calpastatin levels or by expression of dominant negative forms of calpain, may therefore reduce or inhibit muscle atrophy.
Research in this project will explore these possibilities and has the following specific aims:
- Investigate whether targeted over expression of calpastatin will reduce skeletal muscle atrophy in transgenic mice using the hindlimb unweighting model, and;
- Investigate the use of dominant negative forms of calpains to inhibit calpain activity and reduce skeletal muscle protein degradation and atrophy.
Studies will use either the muscle creatine kinase promoter or a fully characterized tetracycline inducible system to express calpastatin or mutated calpains in muscles of transgenic mice or in cultured L8 muscle cells. Muscles will be analyzed for changes in overall size, nucleus/cytoplasm ratio, fiber type, total protein accumulation and degradation rates, and accumulation of individual myofibrillar proteins.
Information gained is expected to broaden our understanding of muscle growth and may suggest approaches for alleviating muscle atrophy in space and on Earth.
This project's funding ended in 2004