Titin: roles in cardiac function and diseases.

The giant protein titin is an essential component of muscle sarcomeres. A single titin molecule spans half a sarcomere and mediates diverse functions along its length by virtue of its unique domains. The A-band of titin functions as a molecular blueprint that defines the length of the thick filaments, the I-band constitutes a molecular spring that determines cell-based passive stiffness, and various domains, including the Z-disk, I-band, and M-line, serve as scaffolds for stretch-sensing signaling pathways that mediate mechanotransduction. This review aims to discuss recent insights into titin's functional roles and their relationship to cardiac function. The role of titin in heart diseases, such as dilated cardiomyopathy and heart failure with preserved ejection fraction, as well as its potential as a therapeutic target, is also discussed.

Acute effects of resistance training at different range of motions on plantar flexion mechanical properties and force.

The effects obtained from resistance training depend on the exercise range of motion (ROM) performed. We aimed to examine the acute effects of different exercise ROM resistance training on the plantar flexor muscles. Eighteen healthy untrained male adults participated in three conditions: calf raises in 1) partial condition [final (short muscle length) partial ROM], 2) full condition (full ROM), and 3) control condition. The ankle dorsiflexion (DF) ROM, passive torque at DF ROM, passive stiffness of muscle-tendon unit, and maximal voluntary isometric contraction (MVC-ISO) torque were measured before and immediately after the interventions. There were significant increases in DF ROM, passive torque at DF ROM, and a decrease in MVC-ISO, but no significant interaction in passive stiffness. Post hoc test, DF ROM demonstrated moderate magnitude increases in the full condition compared to the partial (p = 0.023, d = 0.74) and control (p = 0.003, d = 0.71) conditions. Passive torque at DF ROM also showed moderate magnitude increases in the full condition compared to the control condition (p = 0.016, d = 0.69). MVC-ISO had a moderate magnitude decrease in the full condition compared to the control condition (p = 0.018, d=-0.53). Resistance training in the full ROM acutely increases joint ROM to a greater extent than final partial ROM, most likely due to stretch tolerance.

Hamstring stiffness and injury risk factors during the handball season in female players.

Monitoring the muscle mechanical properties and functions of female athletes throughout their training season is relevant to understand the relationships between these factors and to predict noncontact injuries, which are prevalent among female athletes. The first aim of this study was to determine whether female handball players' passive stiffness of the hamstring muscles is associated with hamstring extensibility, strength of knee flexors and extensors, and lower limb stiffness. Additionally, the study monitored fluctuations in these factors over 25 weeks. The study utilized an isokinetic dynamometer to record hamstring passive stiffness, extensibility, and hamstring and quadriceps strength of 18 young handball players. Lower limb stiffness was determined from a countermovement vertical jump conducted on a force plate. The countermovement jump involved the calculation of the peak force during the eccentric phase and the mean force during the concentric phase. The results showed a positive correlation between hamstring passive stiffness and lower limb stiffness (r = 0.660, p < 0.01), knee flexion and extension strength (r = 0.592, p < 0.01 and r = 0.497, p < 0.05, respectively), and eccentric peak force (r = 0.587, p < 0.01) during jumping. The strength of knee extensors increased significantly after 6 weeks, and hamstring stiffness after 12 weeks of training. In conclusion, the increased hamstring stiffness following training did not match other factors associated with injury risk. Therefore, preventing multifactorial injury risk requires a comprehensive approach, and monitoring one factor alone is insufficient to predict noncontact injuries in female handball players.

Acute and Prolonged Effects of 300 sec of Static, Dynamic, and Combined Stretching on Flexibility and Muscle Force.

Static stretching (SS), dynamic stretching (DS), and combined stretching (CS; i.e., DS+SS) are commonly performed as warm-up exercises. However, the stretching method with the greatest effect on flexibility and performance remains unclear. This randomized crossover trial examined acute and prolonged effects of SS, DS, and CS on range of motion (ROM), peak passive torque (PPT), passive stiffness, and isometric and concentric muscle forces. Twenty healthy young men performed 300 sec of active SS, DS, or CS (150-sec SS followed by 150-sec DS and 150-sec DS followed by 150-sec SS) of the right knee flexors on four separate days, in random order. Subsequently, we measured ROM, PPT, and passive stiffness during passive knee extension. We also measured maximum voluntary isometric and concentric knee flexion forces and surface electromyographic activities during force measurements immediately before, immediately after, and 20 and 60 min after stretching. All stretching methods significantly increased ROM and PPT, while significantly decreasing isometric knee flexion force (all p < 0.05). These changes lasted 60 min after all stretching methods; the increases in ROM and PPT and the decreases in isometric muscle force were similar. All stretching methods also significantly decreased passive stiffness immediately after stretching (all p < 0.05). Decreases in passive stiffness tended to be longer after CS than after SS or DS. Concentric muscle force was decreased after SS and CS (all p < 0.05). On the other hand, concentric muscle force was unchanged after DS, while the decreases in surface electromyographic activities during concentric force measurements after all stretching methods were similar. Our results suggest that 300 sec of SS, DS, and CS have different acute and prolonged effects on flexibility and muscle force.

Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy.

BACKGROUND: Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood. METHODS: We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4-6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales. RESULTS: The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms. CONCLUSIONS: We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.

The immediate effect of unilaterally applied lumbar mobilisations on the passive straight leg raise and ninety-ninety test in asymptomatic adults: A randomised crossover trial.

OBJECTIVES: This study assessed the immediate effect of unilateral posterior-anterior lumbar mobilisations on trunk and lower limb flexibility in asymptomatic individuals. STUDY DESIGN: Randomised cross-over trial. PARTICIPANTS: Twenty-seven participants (age = 26.0 years ±6.4) with no current or recent history of lower back or leg pain/surgery completed the study. MAIN OUTCOME MEASURES: Participants attended two sessions, receiving either grade 3 ('treatment') or grade 1 ('sham') unilateral spinal mobilisations. Outcome measures (modified-modified Schober's test [MMST], ninety-ninety test [NNT], and passive straight-leg raise [PSLR]) were assessed immediately before and after (post-1 and post-2) the intervention. An instrumented hand-held dynamometer was used to measure the change in NNT and PSLR joint angle (deg) and passive stiffness (Nm/deg) pre- and post-intervention. RESULTS: The mean change in PSLR angle at the first (P1) and maximal (P2) point of discomfort following the treatment was 4.8° and 5.5°, and 5.6° and 5.7°, larger than the sham at post-1 and post-2, respectively. There was no effect of the treatment on the PSLR at P1 or P2 for the contralateral limb at either timepoint. There was no effect of the treatment on MMST distance, NNT angle or passive stiffness, or PSLR passive stiffness, for either limb. CONCLUSIONS: Immediate effects of unilateral posterior-anterior lumbar mobilisations in asymptomatic individuals are isolated to treatment side and limited to a small increase in PSLR range, with no change in lumbar motion or the NNT test.

Structure-Function relationships in the skeletal muscle extracellular matrix.

The vast majority of skeletal muscle biomechanical studies have rightly focused on its active contractile properties. However, skeletal muscle passive biomechanical properties have significant clinical impact in aging and disease and are yet incompletely understood. This review focuses on the passive biomechanical properties of the skeletal muscle extracellular matrix (ECM) and suggests aspects of its structural basis. Structural features of the muscle ECM such as perimysial cables, collagen cross-links and endomysial structures have been described, but the way in which these structures combine to create passive biomechanical properties is not completely known. We highlight the presence and organization of perimysial cables. We also demonstrate that the analytical approaches that define passive biomechanical properties are not necessarily straight forward. For example, multiple equations, such as linear, exponential, and polynomial are commonly used to fit raw stress-strain data. Similarly, multiple definitions of zero strain exist that affect muscle biomechanical property calculations. Finally, the appropriate length range over which to measure the mechanical properties is not clear. Overall, this review summarizes our current state of knowledge in these areas and suggests experimental approaches to measuring the structural and functional properties of skeletal muscle.

Are foot posture and morphological deformation associated with ankle plantar flexion isokinetic strength and vertical drop jump kinetics? A principal component analysis.

Static measurements are clinically useful in characterising foot morphology, but it remains unclear to what extent it can influence dynamic lower limb performance. Therefore, the purpose of this study was to investigate if foot posture or foot morphology deformation relates to ankle plantarflexion isokinetic strength and specific kinetics variables during jumping using principal component analysis (PCA). Thirty-eight physically active participants performed drop vertical jump (DVJ) onto force platforms and ankle plantarflexion contractions in different modalities on an isokinetic dynamometer. Foot posture was assessed using the Foot Posture Index-6 item, whereas foot one-, two- and three-dimensional morphological deformation was calculated using the Arch Height Index Measurement System. A PCA was applied to the ankle plantarflexion and kinetics performance data and correlations between PCs and foot parameters measured. The analysis revealed 3 PCs within the ankle plantarflexion and DVJ kinetics variables that captured more than 80% of the variability within the data, but none of them showed significant correlations (r ≤ 0.27) with any foot variables. While foot posture and foot morphological deformation remain of interest in characterising foot morphology across individuals, these findings highlight the lack of clinical relevance of these static evaluations at characterising lower limb and ankle performance.

Effect of body position and external ankle load on the pendulum test in adults.

BACKGROUND: The pendulum test is commonly used to measure passive stiffness about the knee in healthy and clinical populations. While most studies used an upright position, some studies explored different body positions, particularly with children. Additionally, including external ankle load increases the passive motion of the lower leg in children with Down syndrome. Does combining body position and ankle loading affect joint kinematics and muscle activity of the knee extensors during the pendulum test? METHODS: Twenty young adults participated in this study. Three body positions were included: 90-dgree upright, 45-degree incline, and 0-degree supine. Three load conditions were tested: no load (0%), and ankle loads equal to 3% and 6% of the subject's body mass. This resulted in a total of 9 conditions. Five trials were collected for each condition. RESULTS: The upright position elicited a greater number of leg swings and a longer duration of the first knee flexion, while the incline position produced a higher relaxation index. Both ankle load conditions (3% and 6%) increased the magnitude of the first flexion excursion and relaxation index, and the 6% condition produced greater kinematic variables than the 3% load condition. Neither body position nor ankle load elicited muscle activity of the quadriceps. CONCLUSIONS: Body position and external ankle load can affect the kinematics of leg swing during the pendulum test in healthy young adults. Particularly, ankle loads may increase passive motion about the knee. However, we wonder whether small differences across body positions would be clinically relevant.

The impact of age-related increase in passive muscle stiffness on simulated upper limb reaching.

Ageing changes the musculoskeletal and neural systems, potentially affecting a person's ability to perform daily living activities. One of these changes is increased passive stiffness of muscles, but its contribution to performance is difficult to separate experimentally from other ageing effects such as loss of muscle strength or cognitive function. A computational upper limb model was used to study the effects of increasing passive muscle stiffness on reaching performance across the model's workspace (all points reachable with a given model geometry). The simulations indicated that increased muscle stiffness alone caused deterioration of reaching accuracy, starting from the edges of the workspace. Re-tuning the model's control parameters to match the ageing muscle properties does not fully reverse ageing effects but can improve accuracy in selected regions of the workspace. The results suggest that age-related muscle stiffening, isolated from other ageing effects, impairs reaching performance. The model also exhibited oscillatory instability in a few simulations when the controller was tuned to the presence of passive muscle stiffness. This instability is not observed in humans, implying the presence of natural stabilizing strategies, thus pointing to the adaptive capacity of neural control systems as a potential area of future investigation in age-related muscle stiffening.

Comparison of passive torque during shoulder internal rotation before and after a pitching in college baseball pitchers / 体力科学

Previous study reported that baseball pitchers had a decreased shoulder internal rotation (IR) range of motion after pitching. However, whether the decreased range of motion associated with pitching is caused by tightness of the posterior shoulder has not been clarified yet. The joint stiffness in the passive torque can be compared with posterior shoulder tightness before and after pitching. Hence, this study aimed to compare shoulder IR stiffness based on passive torque before and after pitching in baseball pitcher. Eleven health male collage baseball pitchers were recruited. Passive torque during IR (max IR, peak torque and stiffness) of dominant and non-dominant arms was measured using an isokinetic dynamometer. Measurements were taken before, after, and post 24 hours after pitching (105 pitches). It was observed that after pitching, max IR and peak torque were significantly decreased compared to those before pitching. However, there was no difference in the stiffness of passive torque among three measurements. In conclusion, healthy college baseball pitchers have a decreased IR range of motion after pitching. However, this result is not due to posterior shoulder tissue tightness, but because of altered stretch tolerance.

Redox Balance Differentially Affects Biomechanics in Permeabilized Single Muscle Fibres-Active and Passive Force Assessments with the Myorobot.

An oxidizing redox state imposes unique effects on the contractile properties of muscle. Permeabilized fibres show reduced active force generation in the presence of H2O2. However, our knowledge about the muscle fibre's elasticity or flexibility is limited due to shortcomings in assessing the passive stress-strain properties, mostly due to technically limited experimental setups. The MyoRobot is an automated biomechatronics platform that is well-capable of not only investigating calcium responsiveness of active contraction but also features precise stretch actuation to examine the passive stress-strain behaviour. Both were carried out in a consecutive recording sequence on the same fibre for 10 single fibres in total. We denote a significantly diminished maximum calcium-saturated force for fibres exposed to ≥500 µM H2O2, with no marked alteration of the pCa50 value. In contrast to active contraction (e.g., maximum isometric force activation), passive restoration stress (force per area) significantly increases for fibres exposed to an oxidizing environment, as they showed a non-linear stress-strain relationship. Our data support the idea that a highly oxidizing environment promotes non-linear fibre stiffening and confirms that our MyoRobot platform is a suitable tool for investigating redox-related changes in muscle biomechanics.

Effects of stretching intensity on range of motion and muscle stiffness: A narrative review.

BACKGROUND: No review has yet investigated acute and chronic effects of different stretching intensities, including constant-angle (CA) and constant-torque (CT) stretching. OBJECTIVE: This review aimed to investigate the acute and chronic effects of different stretching intensities on the range of motion (ROM) and passive properties. METHODS: PubMed, Scopus, and Google Scholar were used for literature search. Advanced search functions were used to identify original studies using the terms stretching intensity, constant-torque stretching, constant-angle stretching, ROM, passive stiffness, shear elastic modulus in the title or abstract. The keywords were combined using the Boolean operators "AND" and "OR". The search for articles published from inception until 2021 was done in electronic databases. RESULTS AND CONCLUSION: Five studies compared CA and CT stretching. Three studies reported a greater decrease in passive stiffness, and two studies reported a greater ROM increase after CT than CA stretching. Twelve studies investigated the acute effects of different stretching intensities, and six reported a greater ROM increase at higher stretching intensities. Five studies reported a greater decrease in passive stiffness at higher stretching intensities, but three reported no significant differences in passive stiffness among stretching intensities. Five studies investigated the chronic effect, and four reported no significant difference in ROM change among different intensities. Three studies reported no significant changes in passive stiffness after the stretching program. We suggest that the acute effect of higher stretching intensity, including CT stretching, was more effective for changes in ROM and passive stiffness, but the chronic effect was weak.

Calpain-dependent degradation of cytoskeletal proteins as a key mechanism for a reduction in intrinsic passive stiffness of unloaded rat postural muscle.

In mammals, prolonged mechanical unloading results in a significant decrease in passive stiffness of postural muscles. The nature of this phenomenon remains unclear. The aim of the present study was to investigate possible causes for a reduction in rat soleus passive stiffness after 7 and 14 days of unloading (hindlimb suspension, HS). We hypothesized that HS-induced decrease in passive stiffness would be associated with calpain-dependent degradation of cytoskeletal proteins or a decrease in actomyosin interaction. Wistar rats were subjected to HS for 7 and 14 days with or without PD150606 (calpain inhibitor) treatment. Soleus muscles were subjected to biochemical analysis and ex vivo measurements of passive tension with or without blebbistatin treatment (an inhibitor of actomyosin interactions). Passive tension of isolated soleus muscle was significantly reduced after 7- and 14-day HS compared to the control values. PD150606 treatment during 7- and 14-day HS induced an increase in alpha-actinin-2 and -3, desmin contents compared to control, partly prevented a decrease in intact titin (T1) content, and prevented a decrease in soleus passive tension. Incubation of soleus muscle with blebbistatin did not affect HS-induced reductions in specific passive tension in soleus muscle. Our study suggests that calpain-dependent breakdown of cytoskeletal proteins, but not a change in actomyosin interaction, significantly contributes to unloading-induced reductions in intrinsic passive stiffness of rat soleus muscle.

Dysfunctional paraspinal muscles in adult spinal deformity patients lead to increased spinal loading.

PURPOSE: Decreased spinal extensor muscle strength in adult spinal deformity (ASD) patients is well-known but poorly understood; thus, this study aimed to investigate the biomechanical and histopathological properties of paraspinal muscles from ASD patients and predict the effect of altered biomechanical properties on spine loading. METHODS: 68 muscle biopsies were collected from nine ASD patients at L4-L5 (bilateral multifidus and longissimus sampled). The biopsies were tested for muscle fiber and fiber bundle biomechanical properties and histopathology. The small sample size (due to COVID-19) precluded formal statistical analysis, but the properties were compared to literature data. Changes in spinal loading due to the measured properties were predicted by a lumbar spine musculoskeletal model. RESULTS: Single fiber passive elastic moduli were similar to literature values, but in contrast, the fiber bundle moduli exhibited a wide range beyond literature values, with 22% of 171 fiber bundles exhibiting very high elastic moduli, up to 20 times greater. Active contractile specific force was consistently less than literature, with notably 24% of samples exhibiting no contractile ability. Histological analysis of 28 biopsies revealed frequent fibro-fatty replacement with a range of muscle fiber abnormalities. Biomechanical modelling predicted that high muscle stiffness could increase the compressive loads in the spine by over 500%, particularly in flexed postures. DISCUSSION: The histopathological observations suggest diverse mechanisms of potential functional impairment. The large variations observed in muscle biomechanical properties can have a dramatic influence on spinal forces. These early findings highlight the potential key role of the paraspinal muscle in ASD.

Biomechanical Properties of Paraspinal Muscles Influence Spinal Loading-A Musculoskeletal Simulation Study.

Paraspinal muscles are vital to the functioning of the spine. Changes in muscle physiological cross-sectional area significantly affect spinal loading, but the importance of other muscle biomechanical properties remains unclear. This study explored the changes in spinal loading due to variation in five muscle biomechanical properties: passive stiffness, slack sarcomere length (SSL), in situ sarcomere length, specific tension, and pennation angle. An enhanced version of a musculoskeletal simulation model of the thoracolumbar spine with 210 muscle fascicles was used for this study and its predictions were validated for several tasks and multiple postures. Ranges of physiologically realistic values were selected for all five muscle parameters and their influence on L4-L5 intradiscal pressure (IDP) was investigated in standing and 36° flexion. We observed large changes in IDP due to changes in passive stiffness, SSL, in situ sarcomere length, and specific tension, often with interesting interplays between the parameters. For example, for upright standing, a change in stiffness value from one tenth to 10 times the baseline value increased the IDP only by 91% for the baseline model but by 945% when SSL was 0.4 µm shorter. Shorter SSL values and higher stiffnesses led to the largest increases in IDP. More changes were evident in flexion, as sarcomere lengths were longer in that posture and thus the passive curve is more influential. Our results highlight the importance of the muscle force-length curve and the parameters associated with it and motivate further experimental studies on in vivo measurement of those properties.

Repeatability and sensitivity of passive mechanical stiffness measurements in the triceps surae muscle-tendon complex.

Measurements of muscle-tendon unit passive mechanical properties are often used to illustrate acute and chronic responses to a training stimulus. The purpose of this study was to quantify the inter-session repeatability of triceps surae passive stiffness measurements in athletic and non-athletic populations, with the view to discussing its usefulness both as a muscle-tendon profiling tool and a control measure for studies with multiple data collection sessions. The study also aimed to observe the effects of quiet standing on passive stiffness parameters. Twenty-nine men (10 cyclists, nine triathletes, 10 controls) visited the laboratory on three separate occasions, where passive stiffness tests were carried out using an isokinetic dynamometer and B-mode ultrasound. Participants were fully rested on two of the sessions and subjected to 20 min of quiet standing in the other. The passive stiffness assessment generally showed only moderate inter-session repeatability but was still able to detect inter-group differences, with triathletes showing higher passive stiffness than cyclists (p < 0.05). Furthermore, quiet standing impacted passive stiffness by causing a reduction in ankle joint range of motion, although mechanical resistance to stretch in the muscle-tendon unit at a given joint angle was relatively unaffected. These findings show that passive stiffness assessment is appropriate for detecting inter-group differences in the triceps surae and even the effects of a low-intensity task such as quiet standing, despite showing some inter-session variation. However, the inter-session variation suggests that passive stiffness testing might not be suitable as a control measure when testing participants on multiple sessions.

Passive stiffness changes in the lumbar spine following simulated automotive low speed rear-end collisions.

BACKGROUND: Historically, there has been a lack of focus on the lumbar spine during rear impacts because of the perception that the automotive seat back should protect the lumbar spine from injury. As a result, there have been no studies involving human volunteers to address the risk of low back injury in low velocity rear impact collisions. METHODS: A custom-built crash sled was used to simulate rear impact collisions. Randomized collisions were completed with and without lumbar support. Measures of passive stiffness were obtained prior to impact (Pre), immediately post impact (Post) and 24 h post impact (Post-24). Low back pain reporting was monitored for 24 h following impact exposure. FINDINGS: None of the participants developed clinically significant levels of low back pain after impact. Changes in the passive responses persisted after impact for the length of the low stiffness flexion and extension zone. The length of the low stiffness zone was longer in the Post and Post-24 trial for low stiffness flexion and longer in the Post-24 for low stiffness extension. INTERPRETATION: Findings from this investigation demonstrate that during a laboratory-simulation of an 8 km/h rear-impact collision, young healthy adults did not develop low back pain. Changes in the low stiffness zone of the passive flexion/extension curves were observed following impact and persisted for 24 h. Changes in passive stiffness may lead to changes in the loads and load distributions during movement within the passive structures such as the ligaments and intervertebral discs following impacts.

NOS-dependent effects of plantar mechanical stimulation on mechanical characteristics and cytoskeletal proteins in rat soleus muscle during hindlimb suspension.

The study was aimed at investigating the mechanisms and structures which determine mechanical properties of skeletal muscles under gravitational unloading and plantar mechanical stimulation (PMS). We hypothesized that PMS would increase NO production and prevent an unloading-induced reduction in skeletal muscle passive stiffness. Wistar rats were hindlimb suspended and subjected to a daily PMS and one group of stimulated animals was also treated with nitric oxide synthase (NOS) inhibitor (L-NAME). Animals received mechanical stimulation of the feet for 4 h a day throughout 7-day hindlimb suspension (HS) according to a scheme that mimics the normal walking of the animal. Seven-day HS led to a significant reduction in soleus muscle weight by 25%. However, PMS did not prevent the atrophic effect induced by HS. Gravitational unloading led to a significant decrease in maximum isometric force and passive stiffness by 38% and 31%, respectively. The use of PMS prevented a decrease in the maximum isometric strength of the soleus muscle. At the same time, the passive stiffness of the soleus in the PMS group significantly exceeded the control values by 40%. L-NAME (NOS inhibitor) administration attenuated the effect of PMS on passive stiffness and maximum force of the soleus muscle. The content of the studied cytoskeletal proteins (α-actinin-2, α-actinin-3, desmin, titin, nebulin) decreased after 7-day HS, but this decrease was successfully prevented by PMS in a NOS-dependent manner. We also observed significant decreases in mRNA expression levels of α-actinin-2, desmin, and titin after HS, which was prevented by PMS. The study also revealed a significant NOS-dependent effect of PMS on the content of collagen-1a, but not collagen-3a. Thus, PMS during mechanical unloading is able to maintain soleus muscle passive tension and force as well as mRNA transcription and protein contents of cytoskeletal proteins in a NOS-dependent manner.

Molecular Mechanisms of Muscle Tone Impairment under Conditions of Real and Simulated Space Flight.

Kozlovskaya et al. [1] and Grigoriev et al. [2] showed that enormous loss of muscle stiffness (atonia) develops in humans under true (space flight) and simulated microgravity conditions as early as after the first days of exposure. This phenomenon is attributed to the inactivation of slow motor units and called reflectory atonia. However, a lot of evidence indicating that even isolated muscle or a single fiber possesses substantial stiffness was published at the end of the 20th century. This intrinsic stiffness is determined by the active component, i.e. the ability to form actin-myosin cross-bridges during muscle stretch and contraction, as well as by cytoskeletal and extracellular matrix proteins, capable of resisting muscle stretch. The main facts on intrinsic muscle stiffness under conditions of gravitational unloading are considered in this review. The data obtained in studies of humans under dry immersion and rodent hindlimb suspension is analyzed. The results and hypotheses regarding reduced probability of cross-bridge formation in an atrophying muscle due to increased interfilament spacing are described. The evidence of cytoskeletal protein (titin, nebulin, etc.) degradation during gravitational unloading is also discussed. The possible mechanisms underlying structural changes in skeletal muscle collagen and its role in reducing intrinsic muscle stiffness are presented. The molecular mechanisms of changes in intrinsic stiffness during space flight and simulated microgravity are reviewed.