Physiological Mechanisms of Eccentric Contraction and Its Applications: A Role for the Giant Titin Protein

Abstract

When active muscles are stretched, our understanding of muscle function is stretched as well. Our understanding of the molecular mechanisms of concentric contraction has advanced considerably since the advent of the sliding filament theory, whereas mechanisms for increased force production during eccentric contraction are only now becoming clearer. Eccentric contractions play an important role in everyday human movements, including mobility, stability, and muscle strength. Shortly after the sliding filament theory of muscle contraction was introduced, there was a reluctant recognition that muscle behaved as if it contained an "elastic" filament. Jean Hanson and Hugh Huxley referred to this structure as the "S-filament," though their concept gained little traction. This additional filament, the giant titin protein, was identified several decades later, and its roles in muscle contraction are still being discovered. Recent research has demonstrated that, like activation of thin filaments by calcium, titin is also activated in muscle sarcomeres by mechanisms only now being elucidated. The mdm mutation in mice appears to prevent activation of titin, and is a promising model system for investigating mechanisms of titin activation. Titin stiffness appears to increase with muscle force production, providing a mechanism that explains two fundamental properties of eccentric contractions: their high force and low energetic cost. The high force and low energy cost of eccentric contractions makes them particularly well suited for athletic training and rehabilitation. Eccentric exercise is commonly prescribed for treatment of a variety of conditions including sarcopenia, osteoporosis, and tendinosis. Use of eccentric exercise in rehabilitation and athletic training has exploded to include treatment for the elderly, as well as muscle and bone density maintenance for astronauts during long-term space travel. For exercise intolerance and many types of sports injuries, experimental evidence suggests that interventions involving eccentric exercise are demonstrably superior to conventional concentric interventions. Future work promises to advance our understanding of the molecular mechanisms that confer high force and low energy cost to eccentric contraction, as well as signaling mechanisms responsible for the beneficial effects of eccentric exercise in athletic training and rehabilitation.

Keywords: giant sarcomeric proteins; muscle atrophy; muscle intrinsic properties; space travel; sports injury rehabilitation; titin/connectin; winding filament hypothesis.

Figure 1

Layout of titin and other muscle proteins in muscle sarcomeres. Each titin molecule is bound to the thin filaments (blue) in the z-disk, and to the thick filaments (purple) in the A-band. The N2A segment (red) is located between the proximal tandem Ig segments (orange) and the PEVK segment (green). Reproduced with permission from Nishikawa et al. (2012).

Figure 2

Winding filament hypothesis. (A) Upon Ca²⁺ influx, N2A titin (red) binds to thin filaments (blue). (B) Cross-bridges (purple) wind PEVK titin (green) on thin filaments in active muscles. As shown, all titins in the same half-sarcomere must wind in the same direction around actin filaments. Reproduced with permission from Nishikawa et al. (2012).

Figure 3

(A) Passive stretch of muscle sarcomeres. As a sarcomere is stretched beyond its slack length, the proximal tandem Ig segments unfold approximately to their contour length (above). After the proximal tandem Ig segments have reached their contour length, further stretching extends the PEVK segment (below). Adapted from Granzier and Labeit (2004). (B) Active stretch of muscle sarcomeres. Upon activation N2A titin binds to actin (above). Only the PEVK segment (green) extends when active muscle is stretched (below), due to binding of N2A to thin filaments. Reproduced with permission from Nishikawa et al. (2012).

Figure 4

Applications of eccentric training. Eccentric contractions have the properties of high force output and low metabolic demand (top row). There properties allow the musculoskeletal system to be stressed in different ways, compared to conventional concentric exercise, leading to specific training benefits (middle row). These benefits are particularly appropriate for different applications (bottom row). For example, the low cardiac output and low perceived exertion that results from the low energetic cost of eccentric training is particular beneficial for rehabilitation of frail elderly or persons with cardiomyopathy. Adapted from Lindstedt et al. (2001).

Figure 5

Twenty-one frail subjects (mean age 80.2) were enrolled in an 11-week cardiopulmonary rehabilitation program. Control subjects (10) used traditional resistance training with weights (Trad, circles) while the others (11) used an eccentric ergometer (ECC triangles). The Trad group had an insignificant increase in isometric strength (15%, p = 0.12) but a 1.7 s improvement in their timed up and go performance (p = 0.03). In contrast, the ECC subjects had a 60% increase in strength (p = 0.001) and performance on the timed up and go test improved by 4.7 s (p = 0.001); all but one subject changed from high to low fall risk. Reproduced with permission from LaStayo et al. (2003a).