Low Temperature Traps Myosin Motors of Mammalian Muscle in a Refractory State That Prevents Activation

Overview

Journal J Gen Physiol

Specialty Physiology

Date 2019 Sep 27

PMID 31554652

Citations 37

Authors

Marco Caremani

Elisabetta Brunello

Marco Linari

Luca Fusi

Thomas C Irving

David Gore

Gabriella Piazzesi

Malcolm Irving

Vincenzo Lombardi

Massimo Reconditi

Affiliations

Soon will be listed here.

Abstract

Myosin motors in the thick filament of resting striated (skeletal and cardiac) muscle are trapped in an OFF state, in which the motors are packed in helical tracks on the filament surface, inhibiting their interactions with actin and utilization of ATP. To investigate the structural changes induced in the thick filament of mammalian skeletal muscle by changes in temperature, we collected x-ray diffraction patterns from the fast skeletal muscle extensor digitorum longus of the mouse in the temperature range from near physiological (35°C) to 10°C, in which the maximal isometric force ( ) shows a threefold decrease. In resting muscle, x-ray reflections signaling the OFF state of the thick filament indicate that cooling produces a progressive disruption of the OFF state with motors moving away from the ordered helical tracks on the surface of the thick filament. We find that the number of myosin motors in the OFF state at 10°C is half of that at 35°C. At , changes in the x-ray signals that report the fraction and conformation of actin-attached motors can be explained if the threefold decrease in force associated with lowering temperature is due not only to a decrease in the force-generating transition in the actin-attached motors but also to a twofold decrease in the number of such motors. Thus, lowering the temperature reduces to the same extent the fraction of motors in the OFF state at rest and the fraction of motors attached to actin at , suggesting that motors that leave the OFF state accumulate in a disordered refractory state that makes them unavailable for interaction with actin upon stimulation. This regulatory effect of temperature on the thick filament of mammalian skeletal muscle could represent an energetically convenient mechanism for hibernating animals.

Citing Articles

The Mechanism of Modulation of Cardiac Force by Temperature.

Morotti I, Marcello M, Sautariello G, Pertici I, Bianco P, Piazzesi G Int J Mol Sci. 2025; 26(2).

PMID: 39859186 PMC: 11764908. DOI: 10.3390/ijms26020469.

Structural changes in troponin during activation of skeletal and heart muscle determined in situ by polarised fluorescence.

Sevrieva I, Kampourakis T, Irving M Biophys Rev. 2025; 16(6):753-772.

PMID: 39830118 PMC: 11735716. DOI: 10.1007/s12551-024-01245-y.

Reduced ATP turnover during hibernation in relaxed skeletal muscle.

De Napoli C, Schmidt L, Montesel M, Cussonneau L, Sanniti S, Marcucci L Nat Commun. 2025; 16(1):80.

PMID: 39747078 PMC: 11696273. DOI: 10.1038/s41467-024-55565-4.

An integrated picture of the structural pathways controlling the heart performance.

Morotti I, Caremani M, Marcello M, Pertici I, Squarci C, Bianco P Proc Natl Acad Sci U S A. 2024; 121(50):e2410893121.

PMID: 39630866 PMC: 11648670. DOI: 10.1073/pnas.2410893121.

Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.

Childers M, Geeves M, Regnier M Biophys J. 2024; 123(22):3997-4008.

PMID: 39444161 PMC: 11617627. DOI: 10.1016/j.bpj.2024.10.013.

References

HUXLEY A . A note suggesting that the cross-bridge attachment during muscle contraction may take place in two stages. Proc R Soc Lond B Biol Sci. 1973; 183(1070):83-6. DOI: 10.1098/rspb.1973.0006. View

Burkholder T, Fingado B, Baron S, Lieber R . Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol. 1994; 221(2):177-90. DOI: 10.1002/jmor.1052210207. View

Reconditi M, Brunello E, Linari M, Bianco P, Narayanan T, Panine P . Motion of myosin head domains during activation and force development in skeletal muscle. Proc Natl Acad Sci U S A. 2011; 108(17):7236-40. PMC: 3084075. DOI: 10.1073/pnas.1018330108. View

Huxley H, Brown W . The low-angle x-ray diagram of vertebrate striated muscle and its behaviour during contraction and rigor. J Mol Biol. 1967; 30(2):383-434. DOI: 10.1016/s0022-2836(67)80046-9. View

Bershitsky S, Tsaturyan A, Bershitskaya O, Mashanov G, Brown P, Burns R . Muscle force is generated by myosin heads stereospecifically attached to actin. Nature. 1997; 388(6638):186-90. DOI: 10.1038/40651. View

Irving M . Regulation of Contraction by the Thick Filaments in Skeletal Muscle. Biophys J. 2017; 113(12):2579-2594. PMC: 5770512. DOI: 10.1016/j.bpj.2017.09.037. View

Lovell S, Knight P, Harrington W . Fraction of myosin heads bound to thin filaments in rigor fibrils from insect flight and vertebrate muscles. Nature. 1981; 293(5834):664-6. DOI: 10.1038/293664a0. View

Ford L, HUXLEY A, Simmons R . Tension responses to sudden length change in stimulated frog muscle fibres near slack length. J Physiol. 1977; 269(2):441-515. PMC: 1283722. DOI: 10.1113/jphysiol.1977.sp011911. View

Houdusse A, Kalabokis V, Himmel D, Szent-Gyorgyi A, Cohen C . Atomic structure of scallop myosin subfragment S1 complexed with MgADP: a novel conformation of the myosin head. Cell. 1999; 97(4):459-70. DOI: 10.1016/s0092-8674(00)80756-4. View

10.

Cecchi G, Bagni M, Griffiths P, Ashley C, Maeda Y . Detection of radial crossbridge force by lattice spacing changes in intact single muscle fibers. Science. 1990; 250(4986):1409-11. DOI: 10.1126/science.2255911. View

11.

Williams C, Regnier M, Daniel T . Axial and radial forces of cross-bridges depend on lattice spacing. PLoS Comput Biol. 2010; 6(12):e1001018. PMC: 2996315. DOI: 10.1371/journal.pcbi.1001018. View

12.

Fischetti R, Stepanov S, Rosenbaum G, Barrea R, Black E, Gore D . The BioCAT undulator beamline 18ID: a facility for biological non-crystalline diffraction and X-ray absorption spectroscopy at the Advanced Photon Source. J Synchrotron Radiat. 2004; 11(Pt 5):399-405. DOI: 10.1107/S0909049504016760. View

13.

Tsaturyan A . Diffraction by partially occupied helices. Acta Crystallogr A. 2002; 58(Pt 3):292-4. DOI: 10.1107/s0108767302001307. View

14.

Zoghbi M, Woodhead J, Moss R, Craig R . Three-dimensional structure of vertebrate cardiac muscle myosin filaments. Proc Natl Acad Sci U S A. 2008; 105(7):2386-90. PMC: 2268146. DOI: 10.1073/pnas.0708912105. View

15.

Malinchik S, Lednev V . Interpretation of the X-ray diffraction pattern from relaxed skeletal muscle and modelling of the thick filament structure. J Muscle Res Cell Motil. 1992; 13(4):406-19. DOI: 10.1007/BF01738036. View

16.

Xu S, Offer G, Gu J, White H, Yu L . Temperature and ligand dependence of conformation and helical order in myosin filaments. Biochemistry. 2003; 42(2):390-401. DOI: 10.1021/bi026085t. View

17.

Stewart M, Franks-Skiba K, Chen S, Cooke R . Myosin ATP turnover rate is a mechanism involved in thermogenesis in resting skeletal muscle fibers. Proc Natl Acad Sci U S A. 2009; 107(1):430-5. PMC: 2806748. DOI: 10.1073/pnas.0909468107. View

18.

Takacs B, Billington N, Gyimesi M, Kintses B, Malnasi-Csizmadia A, Knight P . Myosin complexed with ADP and blebbistatin reversibly adopts a conformation resembling the start point of the working stroke. Proc Natl Acad Sci U S A. 2010; 107(15):6799-804. PMC: 2872372. DOI: 10.1073/pnas.0907585107. View

19.

Reconditi M, Caremani M, Pinzauti F, Powers J, Narayanan T, Stienen G . Myosin filament activation in the heart is tuned to the mechanical task. Proc Natl Acad Sci U S A. 2017; 114(12):3240-3245. PMC: 5373356. DOI: 10.1073/pnas.1619484114. View

20.

Ranatunga K, Wylie S . Temperature-dependent transitions in isometric contractions of rat muscle. J Physiol. 1983; 339:87-95. PMC: 1199149. DOI: 10.1113/jphysiol.1983.sp014704. View