More roles for the (passive) giant. Focus on “The increase in non-cross-bridge forces after stretch of activated striated muscle is related to titin isoforms”

Abstract

AS STRIATED MUSCLES, the heart and skeletal muscle both act to provide force and motion in animals; the heart rhythmically contracts and produces force to pump blood into the circulation, while skeletal muscle contracts to perform a broad array of precise and dynamic movement. The core molecular mechanism that gives rise to muscle force and movement was described in the seminal studies of A. F. Huxley and R. Niedergerke (6) and H. E. Huxley and J. Hanson, which demonstrated that muscle contraction occurs through the sliding of actin filaments past myosin. A multitude of studies have since continued to identify the force determinants and regulatory components of the striated muscle contractile machinery. In addition to delineating the precise mechanisms by which active muscle contraction occurs, an area not as well understood, but gaining considerable research interest, is the contribution and regulation of force from noncontractile proteins.Titin (also known as "connectin") is the largest known protein in the human body. This multifunctional muscle protein affords structural integrity and noncontractile force production. As a structural protein, titin spans half the length of a striated muscle sarcomere and acts to maintain thick filament alignment over a dynamic range of sarcomere lengths. Titin possesses a springlike quality that generates passive resistance and a restoring element in response to increases in sarcomere length. At sarcomere lengths where there is an absence of cross-bridge interaction, titin is the primary contributor of noncontractile muscle force. The contribution of muscle tension by titin is variable according to a number of key properties. The majority of titin's mass consists of immunoglobulin domains and PEVK (proline, glutamine, valine, and lysinerich) segment repeats derived from differential splicing of isoforms. Additionally, posttranslational modifications and calcium activation can regulate the degree of titin-derived static tension (3). The importance of titin to passive tension in muscle is evident in developmental and disease states, where changes in titin isoforms lead to consequential changes in muscle elastic properties (10). Because of its dynamic function in muscle physiology and pathophysiology, a number of recent studies have attempted to elucidate titin's role in the regulation of noncontractile force.In this issue of American Journal of Physiology-Cell Physiology, Cornachione and colleagues (1) examined the relationship between titin isoforms and non-cross-bridge-derived static tension. The authors built an elaborate single myofibril apparatus with high spatial and time resolution to detect small alterations in passive muscle force. The studies assessed calcium-activated static tension at different sarcomere lengths in three different muscle types (psoas, soleus, and cardiac ventricle) with distinct titin isoforms. The authors observed that static tension was different between muscles, as fast fiber psoas myofibrils produced more tension than slow fiber soleus myofibril...