The molecular structural basis of the braking action of muscle

Q: What is the clinical evidence from this study?

Population: Skeletal muscle braking mechanics (ex vivo mouse extensor digitorum longus muscle) (n=8). Intervention: Constant-velocity mechanical stretch during electrical stimulation vs. Fixed-end contraction before stretch. Primary outcome: Axial movement (Δz) of the centre of mass of the myosin motors away from the thick filament midpoint and muscle force enhancement (MD 0.97 nm).

Q: What does this research mean for the field?

Muscle braking is driven by structural strain in myosin motors combined with sustained filament lattice distortion and volume compression that stores mechanical work and accounts for residual force enhancement. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Cameron Hill; Michaeljohn Kalakoutis; Antonio Andrea Arcidiacono; Atsuki Fukutani; Theyencheri Narayanan; Elisabetta Brunello; Luca Fusi; Malcolm Irving

doi:10.64898/2026.09.25.753934

October 1, 2026Open Access

The molecular structural basis of the braking action of muscle

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Key result

Mechanical stretch increases muscle force by ~40%, driven by axial displacement of myosin motors.

MD +0.97 nm
n=8

Why the study?

Skeletal muscles act as brakes to resist stretching by an external load, but the molecular structural basis of muscle braking has remained obscure.

Key Points

To determine the molecular and structural mechanisms governing how skeletal muscle resists stretching during braking and sustains residual force enhancement.
Isolated mouse extensor digitorum longus muscles (n=8) with an initial mean sarcomere length of 2.56 ± 0.01 µm were stimulated repetitively at 27°C under fixed-end conditions.
Muscles were subjected to a 2.5% stretch at constant velocity (causing ~40 nm filament sliding per half-sarcomere) while structural changes were tracked using equatorial, meridional, and layer-line X-ray reflections.
Force increased by about 40% during stretch and remained 22% higher than pre-stretch levels at the time of the final stimulus, establishing residual force enhancement.
Equatorial X-ray reflection I1,1 decreased by about 30% during stretch with no change in I1,0, and filament lattice volume compressed to about 11% smaller than at rest.
First-order myosin layer line intensity (IML1) fell to about 10% of resting values upon fixed-end activation but showed no change during or after stretch, indicating thick filament activation is unaltered by braking.

Structured PICO

P

Population

8 intact mouse extensor digitorum longus (EDL) muscles stimulated ex vivo at 27°C and stretched by 2.5% of muscle length to investigate the molecular structural basis of muscle braking.

I

Intervention

Repetitive electrical stimulation at 27°C under fixed-end conditions followed by a constant velocity stretch of 2.5% muscle length

C

Comparator

Fixed-end contraction prior to stretch, and comparison with fixed-end tetani or tetani containing unloaded shortening

O

Outcome

Molecular structural changes in myosin motors and the thick and thin filament lattice (measured via time-resolved small-angle X-ray diffraction, ultra-small-angle X-ray diffraction, and X-ray interference) and mechanical force enhancement during and after stretchsurrogate

Main Result

Mean Difference: 0.97

This basic science study demonstrates that skeletal muscle braking and residual force enhancement are mediated by both a rapid, reversible strained conformation in myosin motors and a persistent structural distortion and compression of the thick and thin filament lattice that stores mechanical work.

Limitations

Preclinical ex vivo study conducted in isolated mouse extensor digitorum longus (EDL) muscles
Low signal-to-noise ratio of the second actin-based layer line (IAL2) measurement prevented definitive conclusions regarding stretch effects on thin filament activation
Stretch amplitude and speed were restricted to slow stretches near optimal sarcomere length, preventing kinetic separation of elastic and powerstroke components seen in faster step stretches
Low signal-to-noise ratio of the IAL2 measurement due to axial dispersion of the AL2 layer line and high background scattering in mouse EDL muscles
Measurement of IAL1 is challenging because of high background and partial overlap with the first myosin layer line

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Implication

Reveals structural basis for residual force enhancement in skeletal muscle; leaves open translation to human cardiac or clinical contexts.

Abstract

Skeletal muscles generate force and shortening through a structural ‘powerstroke’ in actin-bound myosin motors linked to ATP hydrolysis, but they also act as brakes to resist stretching by an external load. The molecular structural basis of muscle braking has remained obscure. Here we show that muscle braking is driven both by structural changes in myosin motors and by distortion of the lattice of thick and thin filaments including their M-band and Z-disk connections. A strained motor conformation is established early during stretch, but force continues to increase as thin filaments are displaced from their symmetrical lattice positions, the lateral shear between thick filaments increases, and the lattice volume decreases. Moreover, whilst the motor conformation rapidly recovers after the stretch, the distortion of the filament lattice is largely maintained, storing the work done on the muscle during stretch and accounting for the residual force enhancement after stretch.

Discussion

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Cite This Study

Hill et al. (2026) studied Skeletal muscle braking mechanics (ex vivo mouse extensor digitorum longus muscle) (n=8). Constant-velocity mechanical stretch during electrical stimulation vs. Fixed-end contraction before stretch was evaluated on Axial movement (Δz) of the centre of mass of the myosin motors away from the thick filament midpoint and muscle force enhancement (MD 0.97 nm).

synapsesocial.com/papers/6ae28e0ecbadf70daf6c3fe4 https://doi.org/10.64898/2026.09.25.753934

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The molecular structural basis of the braking action of muscle

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

The molecular structural basis of the braking action of muscle

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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