The mechanisms by which muscle converts chemical to mechanical energy, allowing animal movement, defied explanation for decades. Following the development of the electron microscope and mechanisms of tissue fixation, the ultrastructure of muscle was finally described. Thus was conceived the sliding filament theory, which satisfactorily explained most observable muscle properties. This theory has subsequently been the accepted mechanism of muscle contraction for over six decades. Interestingly, the earliest descriptions of the theory noted that muscle behaved as though in addition to thin and thick filaments, another “superthin” elastic filament must be present. However, as this theoretical filament was not observed, it was not incorporated into the model. Only decades later, and importantly after categorical acceptance of the sliding filament theory, the giant protein titin (AKA connectin) was described: a superthin elastic filament within the muscle fiber. As a filament spanning the sarcomere from Z disk to thick filament, titin is ideally positioned to function as an elastic spring. Once discovered, this largest of known proteins left biologists with two puzzles, one functional and one structural. 1) What is the evolutionary origin of this unique protein? 2) While clearly elastic in structure, why is titin too compliant to function as anin vivo“muscle spring”?

Fig. 1. A. Schematic diagram of passive stretch in skeletal muscle sarcomeres. Top) Passive stretch of muscle sarcomeres. Slack sarcomere, in which the proximal tandem Ig domains (orange) and PEVK segment (green) are short and folded. Middle) As a sarcomere is stretched beyond its slack length, the proximal tandem Ig segments unfold approximately to their contour length. Bottom) After the proximal tandem Ig segments have reached their contour length, further stretching extends the PEVK segment. Adapted from Granzier & Labeit (2004).
b .绕组灯丝的假设。每个肌莫顶部)lecule is bound to the thin filaments (blue) in the I-band, 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). Middle) Upon Ca2+ influx, N2A titin (red) binds to thin filaments (blue). Bottom) Cross-bridges (purple) wind PEVK titin (orange) on thin filaments in active muscle. As shown, all titins in the same half-sarcomere must wind in the same direction around actin filaments. From Nishikawa et al. (2012).

Since its discovery, it has become apparent that titin is one of a nearly ubiquitous group of similar muscle proteins, many of which were described long before titin. Importantly, the evolution of these titin-like proteins preceded the vertebrates. Indeed, similar proteins, called twitchin, sallimus and projectin, are found in all invertebrates except jellyfish; diverse isoforms perform assorted functions. There is now strong evidence that titin is one of a family of closely related muscle filamentous proteins that are ubiquitous in a wide diversity of muscle or muscle-like cells. However, this doesn’t directly bear upon the evolutionary origin of titin-like proteins. While somewhat speculative, evidence suggests that this group of giant elastic proteins may have been co-opted from chromosomal giant proteins responsible for DNA supercoiling.

如果肌功能作为肌肉弹性元件fibers, then when stretched it must store elastic recoil potential energy when stretched. However, when a resting muscle fiber is stretched, very little energy can be stored because titin is passively very compliant. Upon close examination, one finds that titin is composed of a very compliant region (tandem immunoglobulin domains) and a much stiffer region (PEVK), separated by a small “N2A” segment (Fig. 1A). In cardiac muscle titin both segments are greatly reduced in length, and thus the molecule is much stiffer. Importantly, the myocardium only shortens during relaxation, whereas skeletal muscle must function in isometric, and lengthening contractions as well. We believe these observations are directly linked.

During a cardiac cycle, as the ventricle is stretched during filling, the greater the stretch the greater the force of the subsequent contraction. This function is attributed to titin and is only possible if the passive stiffness of titin is high. Because skeletal muscles are organized in pairs of antagonists, however, one might imagine that a dynamically adjustable spring would be necessary to reduce the energy required to contract against a stiff antagonistic muscle. There is now strong evidence that titin stiffness increases in active skeletal muscle, likely by binding to thin filaments when calcium is present. In addition to increasing its stiffness upon muscle activation, several experiments suggest that cross bridges also increase titin stiffness indirectly, perhaps by winding titin around the thin filaments in each cross bridge cycle (Fig. 1B). This “winding filament hypothesis” explains several aspects of muscle physiology that have defied explanation under the standard sliding filament hypothesis.

Kiisa Nishikawa¹,Stan Lindstedt^2
1Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, USA
²Center for Bioengineering Innovation, Northern Arizona University, Flagstaff, Arizona, USA

Publication

Huxleys’ Missing Filament: Form and Function of Titin in Vertebrate Striated Muscle.
Lindstedt S, Nishikawa K
Annu Rev Physiol. 2017 Feb 10

Read offline:

Related Articles:

	Purification and characterization of a better-behaved…Alzheimer’s Disease (AD) is an incurable disease that causes memory, reasoning and thinking to deteriorate over time. AD is marked by brain atrophy and plaque-like deposits of a small peptide…
	How mitochondria "sense" and respond to changes in oxygen…Mitochondria – intracellular organelles – are our organism’s “powerhouse”, the main oxygen sensors that play the signaling role as modulators of oxygen consumption and regulators of the rate of oxygen…
	Autophagy suppression decreases craniofacial bone massMacroautophagy (hereafter autophagy) is the main intracellular degradation mechanism to maintain cellular homeostasis by degrading misfolded proteins, recycling dysfunctional organelles, and generating energy fuels under physiological and pathological conditions. Autophagy…
	The Neuromuscular Junction: a core interpreter in the…Muscle and nerve communicate at the level of a specialized region, namely the neuromuscular junction (NMJ), a synaptic connection where the peripheral nervous system contacts skeletal muscle fibers, governing crucial…
	Layer-dependent fast electron transfer at the…The photo-induced effective interfacial charge separation in Zn phthalocyanine/few-layer graphene heterojunctions has been a promising observation for fabrication of efficient energy-conversion devices. Few-layer graphene are two-dimensional (2D) systems composed of…
	Fullerene soot nanoparticles impose threat to glial cell…Nanotechnology principally deals with engineering or fine tuning of functional matters at their molecular level. The field has generated an exciting scientific attention globally because of the innumerable possibilities it…