Re‑examining the mechanism of eccentric exercise‑induced skeletal muscle damage from the role of the third filament, titin (Review)

Qian,Zhao; Ping,Liu; Xuelin,Zhang

doi:10.3892/br.2023.1703

Re‑examining the mechanism of eccentric exercise‑induced skeletal muscle damage from the role of the third filament, titin (Review)

Authors:
- Zhao Qian
- Liu Ping
- Zhang Xuelin
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Affiliations: College of Physical Education, Qufu Normal University, Jining, Shandong 273165, P.R. China
Published online on: December 1, 2023 https://doi.org/10.3892/br.2023.1703
Article Number: 14
Copyright: © Qian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Intense and unaccustomed eccentric exercise has been extensively studied for its ability to induce muscle damage. However, the underlying mechanism of this phenomenon still requires further clarification. This knowledge gap arises from the need for explanation of the eccentric contraction through the sliding filament theory. The two‑filament sarcomere model, which is consisted of thin and thick filaments, forms the basis of the sliding filament theory. The mechanisms of concentric and isometric contractions at the cellular and molecular levels are effectively described by this model. However, when relying solely on the cross‑bridge swing, the sliding filament theory fails to account for specific observations, such as the stability of the descending limb of the force‑length relationship curve. Recent evidence indicated that titin and the extracellular matrix (ECM) may play a protective role by interacting with the thick and thin filaments. During an eccentric contraction, titin serves as a third filament in the sarcomere, which helps regulate changes in passive force. The two‑filament sarcomere model has limitations in explaining eccentric contraction, thus this compensates for those shortcomings. The present review explored the potential of replacing the two‑filament sarcomere model with a three‑filament sarcomere model, incorporating thin filaments, thick filaments and titin. This revised model offers a more comprehensive explanation of eccentric contraction phenomena. Furthermore, the sliding filament theory was investigated in the context of the three‑filament sarcomere model. The double‑layer protection mechanism, which involves increased titin stiffness and the ECM during eccentric contraction was explored. This mechanism may enhance lateral force transmission between muscle fibers and the ECM, resulting in sarcolemma and ECM shear deformation. These findings provided insight into the mechanism of eccentric exercise‑induced skeletal muscle damage. Considering the three‑filament sarcomere model and the double‑layer protection mechanism, the present review offered a more logical and comprehensive understanding of the mechanism behind eccentric exercise‑induced muscle damage.

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1	Hody S, Croisier JL, Bury T, Rogister B and Leprince P: Eccentric muscle contractions: Risks and benefits. Front Physiol. 10(536)2019.PubMed/NCBI View Article : Google Scholar
2	Liu AS and Zhang XL: Research progress of eccentric training interventions on type 2 diabetes based on matrix metalloproteinases 2, 9 regulating extracellular matrix homeostasis. Chin J Sports Med. 36:1004–1011. 2017.
3	Tomalka A: Eccentric muscle contractions: From single muscle fibre to whole muscle mechanics. Pflugers Arch. 475:421–435. 2023.PubMed/NCBI View Article : Google Scholar
4	Douglas J, Pearson S, Ross A and McGuigan M: Eccentric exercise: Physiological characteristics and acute responses. Sports Med. 47:663–675. 2017.PubMed/NCBI View Article : Google Scholar
5	Annibalini G, Contarelli S, Lucertini F, Guescini M, Maggio S, Ceccaroli P, Gervasi M, Ferri Marini C, Fardetti F, Grassi E, et al: Muscle and systemic molecular responses to a single flywheel based iso-inertial training session in resistance-trained men. Front Physiol. 10(554)2019.PubMed/NCBI View Article : Google Scholar
6	Lovering RM and Brooks SV: Eccentric exercise in aging and diseased skeletal muscle: Good or bad? J Appl Physiol (1985). 116:1439–1445. 2014.PubMed/NCBI View Article : Google Scholar
7	Zhang X, Zhang XL and Xu SS: Exercise and skeletal muscle ultrastructural changes. Chin J Sports Med. 29:109–113. 2010.
8	Keriven H, Sánchez-Sierra A, Miñambres-Martín D, González de la Flor Á, García-Pérez-de-Sevilla G and Domínguez-Balmaseda D: Effects of peripheral electromagnetic stimulation after an eccentric exercise-induced delayed-onset muscle soreness protocol in professional soccer players: A randomized controlled trial. Front Physiol. 14(1206293)2023.PubMed/NCBI View Article : Google Scholar
9	Zhang XL, Gao XJ, Shi JP, Li JP, Zhou Y and Wang R: The mechanism of eccentric exercise-induced skeletal muscle overuse injuries. Chin J Sports Med. 31:1064–1074. 2012.
10	Thirupathi A, Freitas S, Sorato HR, Pedroso GS, Effting PS, Damiani AP, Andrade VM, Nesi RT, Gupta RC, Muller AP and Pinho RA: Modulatory effects of taurine on metabolic and oxidative stress parameters in a mice model of muscle overuse. Nutrition. 54:158–164. 2018.PubMed/NCBI View Article : Google Scholar
11	Zhang XL and Wang RY: The mechanism of overuse injuries: skeletal muscle tensegrity complex imbalance theory. Chin J Sports Med. 32:646–653. 2013.
12	Wang RY: Skeletal muscle and exercise. People's Sports Publishing House, Beijing, 2013.
13	Huxley AF and Niedergerke R: Structural changes in muscle during contraction; interference microscopy of living muscle fibres. Nature. 173:971–973. 1954.PubMed/NCBI View Article : Google Scholar
14	Huxley H and Hanson J: Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature. 173:973–976. 1954.PubMed/NCBI View Article : Google Scholar
15	Herzog W: Mechanisms of enhanced force production in lengthening (eccentric) muscle contractions. J Appl Physiol (1985). 116:1407–1417. 2014.PubMed/NCBI View Article : Google Scholar
16	Novak I and Truskinovsky L: Nonaffine response of skeletal muscles on the ‘descending limb’. Math Mech Solids. 20:697–720. 2015.
17	Zhang X, Zhang XL, Kong M and Ye ML: Changes in lateral force transmission of skeletal muscle induced by acute eccentric exercise and acupuncture intervention effect. Chin J Sport Sci Technol. 54:94–108. 2018.
18	Kong M, Zhang X, Ye ML and Zhang XL: Changes of perimysial junctional plates induced by excessive eccentric training and the effects of acupuncture intervention. Sheng Li Xue Bao. 69:17–32. 2017.PubMed/NCBI(In Chinese).
19	Hanson J and Huxley HE: Structural basis of the cross-striations in muscle. Nature. 172:530–532. 1953.PubMed/NCBI View Article : Google Scholar
20	Huxley AF: Reflections on muscle. Liverpool UK: Liverpool University Press, 1980.
21	Herzog W: The role of titin in eccentric muscle contraction. J Exp Biol. 217:2825–2833. 2014.PubMed/NCBI View Article : Google Scholar
22	Horowits R and Podolsky RJ: The positional stability of thick filaments in activated skeletal muscle depends on sarcomere length: Evidence for the role of titin filaments. J Cell Biol. 105:2217–2223. 1987.PubMed/NCBI View Article : Google Scholar
23	Zhao Q and Zhang XL: Discussion on revision of the sliding filament theory to resolve problems of eccentric contraction mechanism. Acta Physiol Sinica. 73:143–147. 2021.
24	Herzog W, Schappacher G, Duvall M, Leonard TR and Herzog JA: Residual force enhancement following eccentric contractions: A new mechanism involving titin. Physiology (Bethesda). 31:300–312. 2016.PubMed/NCBI View Article : Google Scholar
25	Huxley HE: Electron microscope studies of the organisation of the filaments in striated muscle. Biochim Biophys Acta. 12:387–394. 1953.PubMed/NCBI View Article : Google Scholar
26	Huxley AF: Muscle structure and theories of contraction. Prog Biophys Biophys Chem. 7:255–318. 1957.PubMed/NCBI
27	Huxley HE: The mechanism of muscular contraction. Science. 164:1356–1365. 1969.PubMed/NCBI View Article : Google Scholar
28	Huxley AF and Simmons RM: Proposed mechanism of force generation in striated muscle. Nature. 233:533–538. 1971.PubMed/NCBI View Article : Google Scholar
29	Morgan DL, Whitehead NP, Wise AK, Gregory JE and Proske U: Tension changes in the cat soleus muscle following slow stretch or shortening of the contracting muscle. J Physiol. 522:503–513. 2000.PubMed/NCBI View Article : Google Scholar
30	Iwazumi T: Molecular mechanism of muscle contraction. Physiol Chem Phys Med NMR. 21:187–219. 1989.
31	Morgan DL: New insights into the behavior of muscle during active lengthening. Biophys J. 57:209–221. 1990.PubMed/NCBI View Article : Google Scholar
32	Morgan DL and Proske U: Popping sarcomere hypothesis explains stretch-induced muscle damage. Clin Exp Pharmacol Physiol. 31:541–545. 2004.PubMed/NCBI View Article : Google Scholar
33	Rassier DE, Herzog W and Pollack GH: Dynamics of individual sarcomeres during and after stretch in activated single myofibrils. Proc Biol Sci. 270:1735–1740. 2003.PubMed/NCBI View Article : Google Scholar
34	Rassier DE, Herzog W and Pollack GH: Stretch-induced force enhancement and stability of skeletal muscle myofibrils. Adv Exp Med Biol. 538:501–515. 2003.PubMed/NCBI View Article : Google Scholar
35	Dos Remedios CG: Comparative studies on striated muscle. PhD thesis, University of Sydney, 1965.
36	Maruyama K: Connectin, an elastic protein from myofibrils. J Biochem. 80:405–407. 1976.PubMed/NCBI View Article : Google Scholar
37	Wang K, McClure J and Tu A: Titin: Major myofibrillar components of striated muscle. Proc Natl Acad Sci USA. 76:3698–3702. 1979.PubMed/NCBI View Article : Google Scholar
38	Fürst DO, Osborn M, Nave R and Weber K: The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: A map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol. 106:1563–1572. 1988.PubMed/NCBI View Article : Google Scholar
39	Linke WA and Krüger M: The giant protein titin as an integrator of myocyte signaling pathways. Physiology (Bethesda). 25:186–198. 2010.PubMed/NCBI View Article : Google Scholar
40	Holt NC: Beyond bouncy gaits: The role of multiscale compliance in skeletal muscle performance. J Exp Zool A Ecol Integr Physiol. 333:50–59. 2020.PubMed/NCBI View Article : Google Scholar
41	Nishikawa KC, Monroy JA, Uyeno TE, Yeo SH, Pai DK and Lindstedt SL: Is titin a ‘winding filament’? A new twist on muscle contraction. Proc Biol Sci. 279:981–990. 2012.PubMed/NCBI View Article : Google Scholar
42	DuVall MM, Jinha A, Schappacher-Tilp G, Leonard TR and Herzog W: Differences in titin segmental elongation between passive and active stretch in skeletal muscle. J Exp Biol. 220:4418–4425. 2017.PubMed/NCBI View Article : Google Scholar
43	Labeit D, Watanabe K, Witt C, Fujita H, Wu Y, Lahmers S, Funck T, Labeit S and Granzier H: Calcium-dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci USA. 100:13716–13721. 2003.PubMed/NCBI View Article : Google Scholar
44	Leonard TR and Herzog W: Regulation of muscle force in the absence of actin-myosin-based cross-bridge interaction. Am J Physiol Cell Physiol. 299:C14–C20. 2010.PubMed/NCBI View Article : Google Scholar
45	Brynnel A, Hernandez Y, Kiss B, Lindqvist J, Adler M, Kolb J, van der Pijl R, Gohlke J, Strom J, Smith J, et al: Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy. Elife. 7(e40532)2018.PubMed/NCBI View Article : Google Scholar
46	Weidner S, Tomalka A, Rode C and Siebert T: How velocity impacts eccentric force generation of fully activated skinned skeletal muscle fibers in long stretches. J Appl Physiol (1985). 133:223–233. 2022.PubMed/NCBI View Article : Google Scholar
47	Shi J, Watanabe D and Wada M: Eccentric muscle contraction potentiates titin stiffness-related contractile properties in rat fast-twitch muscles. J Appl Physiol (1985). 133:710–720. 2022.PubMed/NCBI View Article : Google Scholar
48	Owens DJ, Twist C, Cobley JN, Howatson G and Close GL: Exercise-induced muscle damage: What is it, what causes it and what are the nutritional solutions? Eur J Sport Sci. 19:71–85. 2019.PubMed/NCBI View Article : Google Scholar
49	Jørgensen A, Foster PP, Eftedal I, Wisløff U, Paulsen G, Havnes MB and Brubakk AO: Exercise-induced myofibrillar disruption with sarcolemmal integrity prior to simulated diving has no effect on vascular bubble formation in rats. Eur J Appl Physiol. 113:1189–1198. 2013.PubMed/NCBI View Article : Google Scholar
50	Yu JG, Liu JX, Carlsson L, Thornell LE and Stål PS: Re-evaluation of sarcolemma injury and muscle swelling in human skeletal muscles after eccentric exercise. PLoS One. 8(e62056)2013.PubMed/NCBI View Article : Google Scholar
51	Powers JD, Bianco P, Pertici I, Reconditi M, Lombardi V and Piazzesi G: Contracting striated muscle has a dynamic I-band spring with an undamped stiffness 100 times larger than the passive stiffness. J Physiol. 598:331–345. 2020.PubMed/NCBI View Article : Google Scholar
52	Lieber RL and Binder-Markey BI: . Biochemical and structural basis of the passive mechanical properties of whole skeletal muscle. J Physiol. 599:3809–3823. 2021.PubMed/NCBI View Article : Google Scholar
53	Ramaswamy KS, Palmer ML, van der Meulen JH, Renoux A, Kostrominova TY, Michele DE and Faulkner JA: Lateral transmission of force is impaired in skeletal muscles of dystrophic mice and very old rats. J Physiol. 589:1195–1208. 2011.PubMed/NCBI View Article : Google Scholar
54	Minato K, Yoshimoto Y, Kurosawa T, Watanabe K, Kawashima H, Ikemoto-Uezumi M and Uezumi A: Measurement of lateral transmission of force in the extensor digitorum longus muscle of young and old mice. Int J Mol Sci. 22(12356)2021.PubMed/NCBI View Article : Google Scholar
55	Le S, Yu M, Hovan L, Zhao Z, Ervasti J and Yan J: Dystrophin as a molecular shock absorber. ACS Nano. 12:12140–12148. 2018.PubMed/NCBI View Article : Google Scholar
56	Lo HP, Hall TE and Parton RG: . Mechanoprotection by skeletal muscle caveolae. Bioarchitecture. 6:22–27. 2016.PubMed/NCBI View Article : Google Scholar
57	Boppart MD, Volker SE, Alexander N, Burkin DJ and Kaufman SJ: . Exercise promotes alpha7 integrin gene transcription and protection of skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 295:R1623–R1630. 2008.PubMed/NCBI View Article : Google Scholar
58	Zhang BT, Whitehead NP, Gervasio OL, Reardon TF, Vale M, Fatkin D, Dietrich A, Yeung EW and Allen DG: Pathways of Ca²⁺ entry and cytoskeletal damage following eccentric contractions in mouse skeletal muscle. J Appl Physiol (1985). 112:2077–2086. 2012.PubMed/NCBI View Article : Google Scholar