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.

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.

After an initial increase, isovelocity elongation of a muscle fiber can lead to diminishing (referred to as Give in the literature) and subsequently increasing force. How the stretch velocity affects this behavior in slow-twitch fibers remains largely unexplored. Here, we stretched fully activated individual rat soleus muscle fibers from 0.85 to 1.3 optimal fiber length at stretch velocities of 0.01, 0.1, and 1 maximum shortening velocity, v_max, and compared the results with those of rat EDL fast-twitch fibers obtained in similar experimental conditions. In soleus muscle fibers, Give was 7%, 18%, and 44% of maximum isometric force for 0.01, 0.1, and 1 v_max, respectively. As in EDL fibers, the force increased nearly linearly in the second half of the stretch, although the number of crossbridges decreased, and its slope increased with stretch velocity. Our findings are consistent with the concept of a forceful detachment and subsequent crossbridge reattachment in the stretch’s first phase and a strong viscoelastic titin contribution to fiber force in the second phase of the stretch. Interestingly, we found interaction effects of stretch velocity and fiber type on force parameters in both stretch phases, hinting at fiber type-specific differences in crossbridge and titin contributions to eccentric force. Whether fiber type-specific combined XB and non-XB models can explain these effects or if they hint at some not fully understood properties of muscle contraction remains to be shown. These results may stimulate new optimization perspectives in sports training and provide a better understanding of structure–function relations of muscle proteins.

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 <0.001, extensor digitorum longus: +66.0%, P =ns) contractile function and titin phosphorylation (soleus: −35.4%, P <0.001, extensor digitorum longus: −40.2%, P <0.001), while preventing atrophy development (soleus: +49%, 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.

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.