André Tomalka

Stretch–shortening cycles (SSCs) enhance force and mechanical work compared with pure shortening contractions and are fundamental to locomotion. Although SSC mechanics are well studied, it remains unclear whether mechanical cycle-to-cycle carryover effects persist across repeated SSCs despite brief deactivation or inhibition of cross-bridge (XB) force production. To address this, single-skinned fibres from rat extensor digitorum longus muscles (n=21) underwent three consecutive SSCs at a slow velocity (1% maximal shortening velocity). Fibres were activated isometrically for 20 s before SSC1, whereas SSC2 and SSC3 were each preceded by 4 s of deactivation followed by 20 s of isometric activation. Experiments were performed under control conditions and with blebbistatin to inhibit XB force production. Repeated SSCs produced progressive performance enhancements under both conditions despite brief deactivation. From SSC1 to SSC3, peak force (Fpeak) increased by 14.6% and total SSC work (WorkSSC) by 50.1% under control conditions, and by 37.5% and 67.6%, respectively, with blebbistatin. Increased short-range stiffness under control conditions suggests XB-mediated stretch resistance, whereas persistent increases during XB inhibition indicate contributions from non-XB structures, particularly titin. These findings support a sarcomeric memory effect that enhances stretch resistance and work during repeated SSCs.

BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment. METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses. RESULTS: HFpEF rats exhibited reduced cardiolipin levels (−6.8%, P =0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, P =0.041, extensor digitorum longus: +10.9%, P =0.016) and single-fiber (soleus: +173.2%, P P =ns) contractile function and titin phosphorylation (soleus: −35.4%, P P P =0.001, extensor digitorum longus: +54.8%, P <0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity. CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.

Eccentric muscle contractions are essential for locomotion and daily activities. Force during these contractions depends on both cross‐bridge (XB) and non‐cross‐bridge (non‐XB) elements, including titin, with contributions varying by fibre type and contraction velocity. Despite their importance, mechanisms of force generation during prolonged stretches remain unclear. Chemical XB inhibitors are commonly used to separate XB and non‐XB contributions, but their effects have not been systematically compared under identical conditions. We measured eccentric force in single permeabilised fibres from fast‐twitch rat extensor digitorum longus (EDL) and slow‐twitch soleus (SOL) muscles. Fibres were treated with blebbistatin (Bleb), 2,3‐butanedione monoxime (BDM), or N ‐benzyl‐ p ‐toluene sulphonamide (BTS) and stretched from 0.85 to 1.3 times optimal length at three velocities (0.01, 0.1 and 1.0 maximal contraction velocity). XB inhibition produced fibre‐type‐dependent effects on early‐ and late‐stretch force (slope ₁ , slope ₂ ) and on end‐of‐stretch force ( s _e ). Stretch velocity and the type of XB inhibitor influenced s _e in both SOL and EDL fibres. However, in EDL fibres, s _e did not differ significantly between XB inhibitors and showed velocity‐dependent effects under Bleb and BTS only, but not under BDM. Stretch‐induced forces were less reduced than isometric forces, indicating substantial stretch‐dependent non‐XB contributions. These results show that eccentric force arises from coordinated XB and non‐XB mechanisms in a fibre‐type‐dependent manner and highlight Bleb as an effective tool for probing these contributions.

Force generation dynamics in native muscle tissues have been stringently optimized by evolution. Realizing similar contractile dynamics in a widely available biomaterial and subsequently fabricating macroscopic functional modules from them remains challenging. Herein, we tailor two-photon stereolithography to 3D print synthetic muscles made from bovine serum albumin to realize 1 mm long contractile fibers. We show that pH-dependent contractions in these synthetic muscles follow parabolic force-length relationships similar to biological muscles. Achieved stress outputs of 0.78 ± 0.13 N cm ⁻² were within an order of magnitude of smooth and cardiac muscle. Stretch-shortening work loops performed under different strain rates in turn revealed a viscoelastic behavior and significant velocity dependence of work and net power, more similar to skeletal muscle. That an isotropic protein hydrogel can achieve such dynamics, reinforces the notion that these are not limited to sarcomere-level ordering and suggests a more general design space for non-canonical conformational dynamics to engineer performance improvements in artificial muscle materials.

Objective: This study investigates the relationship between motion sickness and body movements experienced by car passengers during non-driving related activities. Background: The theory linking motion sickness to postural instability is well-documented in static environments. However, evidence supporting this theory in dynamic environments, such as moving vehicles, is still lacking. Method: Using an experimental approach replicating a naturalistic 15-min car ride, 56 participants were equipped with an in-ear sensor to measure the linear accelerations of the head. Participants reported their motion sickness severity at 3-min intervals during the experiment and once more post experimentation. Additionally, the UniPG numerical model was used to estimate motion sickness severity. Results: The study identified significant relationships between specific head movement patterns and motion sickness severity, even though the overall symptoms reported were mild. Nonlinear interactions were identified between the standard deviation ( p = .032) and the skewness ( p = .028) of longitudinal head acceleration, as well as for the skewness ( p = .004) and kurtosis ( p = .008) of lateral head acceleration. Predictions from the UniPG model correlated with subjective ratings for 67% of participants with some motion sickness symptoms. Conclusion: Highly variable longitudinal movements appear more tolerable when lateral movements remain symmetric; however, when both variability and asymmetry in head movements are present together in a specific pattern, they may exacerbate motion sickness symptoms. Application: Incorporating motion sickness prediction models in vehicles, based on the measurement of head movements, might improve detection of the escalation of symptoms in car passengers.

Stretch–shortening cycles (SSCs) involve muscle lengthening (eccentric contractions) instantly followed by shortening (concentric contractions). This combination enhances force, work and power output compared with pure shortening contractions, which is known as the SSC effect. Recent evidence indicates both cross-bridge (XB)-based and non-XB-based (e.g. titin) structures contribute to this effect. This study analysed force re-development following SSCs and pure shortening contractions to gain further insight into the roles of XB and non-XB structures regarding the SSC effect. Experiments were conducted on rat soleus muscle fibres (n=16) with different SSC velocities (30%, 60% and 85% of maximum shortening velocity) and constant stretch–shortening magnitudes (18% of optimum length). The XB inhibitor blebbistatin was used to distinguish between XB and non-XB contributions to force generation. The results showed SSCs led to significantly greater [mean±s.d. 1.02±0.15 versus 0.68±0.09 (ΔF/Δt); t62=8.61, P<0.001, d=2.79) and faster (75 ms versus 205 ms; t62=−6.37, P<0.001, d=−1.48) force re-development compared with pure shortening contractions in the control treatment. In the blebbistatin treatment, SSCs still resulted in greater [0.11±0.03 versus 0.06±0.01 (ΔF/Δt); t62=8.00, P<0.001, d=2.24) and faster (3010±1631 versus 7916±3230 ms; t62=−8.00, P<0.001, d=−1.92) force re-development compared with pure shortening contractions. These findings deepen our understanding of the SSC effect, underscoring the involvement of non-XB structures such as titin in modulating force production. This modulation is likely to involve complex mechanosensory coupling from stretch to signal transmission during muscle contraction.

Eccentric muscle loading encompasses several unique features compared to other types of contractions. These features include increased force, work, and performance at decreased oxygen consumption, reduced metabolic cost, improved energy efficiency, as well as decreased muscle activity. This review summarises explanatory approaches to long-standing questions in terms of muscular contraction dynamics and molecular and cellular mechanisms underlying eccentric muscle loading. Moreover, this article intends to underscore the functional link between sarcomeric components, emphasising the fundamental role of titin in skeletal muscle. The giant filament titin reveals versatile functions ranging from sarcomere organisation and maintenance, providing passive tension and elasticity, and operates as a mechanosensory and signalling platform. Structurally, titin consists of a viscoelastic spring segment that allows activation-dependent coupling to actin. This titin-actin interaction can explain linear force increases in active lengthening experiments in biological systems. A three-filament model of skeletal muscle force production (mediated by titin) is supposed to overcome significant deviations between experimental observations and predictions by the classic sliding-filament and cross-bridge theories. Taken together, this review intends to contribute to a more detailed understanding of overall muscle behaviour and force generation—from a microscopic sarcomere level to a macroscopic multi-joint muscle level—impacting muscle modelling, the understanding of muscle function, and disease.

How myofilaments operate at short mammalian skeletal muscle lengths is unknown. A common assumption is that thick (myosin-containing) filaments get compressed at the Z-disc. We provide ultrastructural evidence of sarcomeres contracting down to 0.44 µm—approximately a quarter of thick filament resting length—in long-lasting contractions while apparently keeping a regular, parallel thick filament arrangement. Sarcomeres produced force at such extremely short lengths. Furthermore, sarcomeres adopted a bimodal length distribution with both modes below lengths where sarcomeres are expected to generate force in classic force–length measurements. Mammalian fibres did not restore resting length but remained short after deactivation, as previously reported for amphibian fibres, and showed increased forces during passive re-elongation. These findings are incompatible with viscoelastic thick filament compression but agree with predictions of a model incorporating thick filament sliding through the Z-disc. This more coherent picture of mechanical mammalian skeletal fibre functioning opens new perspectives on muscle physiology.

Ecccentric muscle contractions are fundamental to everyday life. They occur markedly in jumping, running, and accidents. Following an initial force rise, stretching of a fully activated muscle can result in a phase of decreasing force (“Give”) followed by force redevelopment. However, how the stretch velocity affects “Give” and force redevelopment remains largely unknown. We investigated the force produced by fully activated single-skinned fibers of rat extensor digitorum longus muscles during long stretches. Fibers were pulled from length 0.85 to 1.3 optimal fiber length at a rate of 1%, 10%, and 100% of the estimated maximum shortening velocity. “Give” was absent in slow stretches. Medium and fast stretches yielded a clear “Give.” After the initial force peak, forces decreased by 11.2% and 27.8% relative to the initial peak force before rising again. During the last half of the stretch (from 1.07 to 1.3 optimal fiber length, which is within the range of the expected descending limb of the force-length relationship), the linear force slope tripled from slow to medium stretch and increased further by 60% from medium to fast stretch. These results are compatible with forcible cross-bridge detachment and redevelopment of a cross-bridge distribution, and a viscoelastic titin contribution to fiber force. Accounting for these results can improve muscle models and predictions of multibody simulations. NEW & NOTEWORTHY Eccentric muscle contractions are part of our daily lives. We found that force increased monotonically during slow stretches of fully activated muscle fibers, whereas higher stretch velocities resulted in an increasing drop in force after an initial increase and a final steeper rise in force. Cross-bridges cannot explain the observed force traces. This requires a viscoelastic non-cross-bridge contribution. Considering these results can improve muscle models and predictions of multibody simulations.