Myofibril breakdown during atrophy is an ordered tightly regulated process.
The fundamental contractile machinery in muscle, the myofibrils, is a precisely aligned filament system of actin thin filaments and myosin thick filaments, which are organized in repeated units of sarcomeres. The lateral boundaries of the sarcomere are defined by the Z-lines, which constitute the anchoring site for the thin filaments, as well as two other filament systems, titin and nebulin. The thin filaments extend toward the middle of the sarcomere, where they interdigitate with myosin to generate force. Two heavy chains of myosin form the backbone of the thick filament, and two regulatory (MyLC2) and essential (MyLC1) light chains bind the myosin head, which extends from the thick filament to interact with actin and drive ATP-dependent muscle contraction. These light chains, and other structural components including myosin-binding protein C, are required for thick filament stability and normal contractility.
Upon disuse, denervation or aging, and in systemic catabolic states, including cancer cachexia, diabetes, sepsis, and AIDS, myofibril destruction is accelerated leading to muscle wasting, disability and mortality. Since myofibrils comprise the majority of muscle proteins and are responsible for force production, their loss during atrophy ultimately leads to reduced strength, frailty and disability. The mechanism for myofibril breakdown during atrophy has long been uncertain although the ubiquitin-proteasome system seems to play a major role. This process must be ordered and tightly regulated because muscles continue to contract even during rapid atrophy (e.g. fasting, cancer cachexia).
Our in vitro model for disuse atrophy is a Round Positioning Machine, which imitates microgravity. We grow on this myotubes to study atrophy-induced by reduced load (as occurs on e.g. inactivity, aging, immobilization). Chick embryos or zebrafish can be grown on it too! We are happy to collaborate!
One of our lab’s goals is to understand how does the intricate and complex structure of myofibrils disassemble during atrophy. Using a sophisticated in vivo electroporation technique, as well as biochemical, proteomic, and genomic approaches we investigate the specific roles of ubiquitin-proteasome-system components in catalyzing myofibril destruction in different types of atrophy.