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.

Effects of a titin mutation on negative work during stretch-shortening cycles in skeletal muscles

“…It has been suggested that calcium-dependent titinactin interactions may contribute to increased titin stiffness in active muscle (Herzog et al, 2016;Nishikawa, 2016;Schappacher-Tilp et al, 2015). The mechanism(s) responsible for the increase in titin stiffness during activation appear to be impaired in mdm muscles (Powers et al, 2016), and are currently under investigation (Hessel et al, 2017;Nishikawa, 2016).…”

“…It is therefore likely that earlier studies (Linari et al, 2003;Pinniger et al, 2006) underestimated titin's contribution to energy storage during stretch. Increased titin stiffness in active muscle is thought to explain residual force enhancement (Leonard and Herzog, 2010;Herzog, 2014;Herzog et al, 2016;Hessel et al, 2017;Lindstedt and Nishikawa, 2017;Nocella et al, 2014). Due to its length and viscoelastic properties (Bianco et al, 2007;Mártonfalvi et al, 2014), titin is uniquely suited to store kinetic energy during stretch and also to dissipate energy as heat during shortening.…”

The Work of Titin Protein Folding as a Major Driver in Muscle Contraction

“…While it is beyond doubt that the chemical energy of ATP powers the cycling of myosin motors as they slide along the actin filaments during a contraction (26–29), the role of titin during shortening is poorly understood and requires the sustained focus of the muscle community to be clarified. There are several competing theories for how titin might generate force during a muscle contraction (22, 30–32), but experiments at the muscle fiber level have failed to elucidate a molecular mechanism. Over the last 20 years, technical advances in force spectroscopy combined with protein engineering have been used to study titin dynamics under force (10, 33–39).…”

Severe thermoregulatory deficiencies in mice with a deletion in the titin gene

“…Mice homozygous for the mdm mutation exhibit severe and progressive degeneration of skeletal muscles and lower body mass, stiffer gait and reduced lifespan compared with wild-type (WT) littermates (Garvey et al, 2002;Huebsch et al, 2005;Lopez et al, 2008). Muscle in mdm mice has higher passive stiffness than WT muscle (Hessel et al, 2017;Lopez et al, 2008;Monroy et al, 2017). Taylor-Burt et al (2015) demonstrated in vitro that mdm mice have lower active muscle stiffness as well and a lower tremor frequency during ST.…”