Continuous Use During Disuse: Mechanisms and Effects of Spontaneous Activity of Unloaded Postural Muscle.

In most mammals, postural soleus muscles are involved in the maintenance of the stability of the body in the gravitational field of Earth. It is well established that immediately after a laboratory rat is exposed to conditions of weightlessness (parabolic flight) or simulated microgravity (hindlimb suspension/unloading), a sharp decrease in soleus muscle electrical activity occurs. However, starting from the 3rd day of mechanical unloading, soleus muscle electrical activity begins to increase and reaches baseline levels approximately by the 14th day of hindlimb suspension.

Antioxidant mito-TEMPO prevents the increase in tropomyosin oxidation and mitochondrial calcium accumulation under 7-day rat hindlimb suspension.

After the first day of muscle disuse (unloading) mitochondria-derived ROS accumulate in the postural-tonic soleus muscle. It is known that excess of ROS can lead to the accumulation of intramitochondrial calcium and overload of mitochondria with calcium, can negatively affect mitochondrial function and fatigue resistance of soleus muscle. We assumed that the use of mitochondrial ROS scavenger mito-TEMPO will be able to prevent the unloading-induced disruption of mitochondrial functions and will help maintain soleus muscle fatigue resistance.

Molecular Signaling Effects behind the Spontaneous Soleus Muscle Activity Induced by 7-Day Rat Hindlimb Suspension.

The elimination of ground reaction force (support withdrawal) vastly affects slow postural muscles in terms of their regulation and structure. One of the effects of support withdrawal in this study was an immediate postural muscle inactivation, followed by the daily gradual development of spontaneous activity of the slow postural soleus muscle in response to rat hindlimb suspension to mimic space flight. The origin of this activity is somewhat akin to muscle spasticity after spinal cord injuries and is the result of KCC2 content decline in the spinal cord's motor neurons.

Mechanical interaction of myosin and native thin filament in the disused rat soleus muscle.

The disuse of skeletal limb muscles occurs in a variety of conditions, yet our comprehension of the molecular mechanisms involved in adaptation to disuse remains incomplete. We studied the mechanical characteristics of actin-myosin interaction using an in vitro motility assay and isoform composition of myosin heavy and light chains by dint of SDS-PAGE in soleus muscle of both control and hindlimb-unloaded rats. 14 days of hindlimb unloading led to the increased maximum sliding velocity of actin, reconstituted, and native thin filaments over rat soleus muscle myosin by 24 %, 19 %, and 20 %, respectively.

P2Y1 and P2Y2 receptors differ in their role in the regulation of signaling pathways during unloading-induced rat soleus muscle atrophy.

The current study aimed to investigate the hypothesis that purinergic receptors P2Y1 and P2Y2 play a regulatory role in gene expression in unloaded muscle. ATP is released from cells through pannexin channels, and it interacts with P2Y1 and P2Y2 receptors, leading to the activation of markers of protein catabolism and a reduction in protein synthesis. To test this hypothesis thirty-two rats were randomly divided into four groups (8 per group): a non-treated control group (C), a group subjected to three days of hindlimb unloading with a placebo (HS), a group subjected to three days of hindlimb unloading treated with a P2Y1 receptor inhibitor, MRS2179 (HSM), and a group subjected to three days of hindlimb unloading treated with a P2Y2 receptor inhibitor, AR-C 118925XX (HSA).

Six-day dry immersion leads to downregulation of slow-fiber type and mitochondria-related genes expression.

The soleus muscle in humans is responsible for maintaining an upright posture and participating in walking and running. Under muscle disuse, it undergoes molecular signaling changes that result in altered force and work capacity. The triggering mechanisms and pathways of these changes are not yet fully understood.

The Effect of SERCA Activation on Functional Characteristics and Signaling of Rat Soleus Muscle upon 7 Days of Unloading.

Skeletal muscle abnormalities and atrophy during unloading are accompanied by the accumulation of excess calcium in the sarcoplasm. We hypothesized that calcium accumulation may occur, among other mechanisms, due to the inhibition of sarco/endoplasmic reticulum Ca-ATPase (SERCA) activity. Consequently, the use of the SERCA activator will reduce the level of calcium in the sarcoplasm and prevent the negative consequences of muscle unloading.

A Prochlorperazine-Induced Decrease in Autonomous Muscle Activity during Hindlimb Unloading Is Accompanied by Preserved Slow Myosin mRNA Expression.

Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so this transformation leads to a decline in muscle function. Prochlorperazine injections previously were shown to attenuate autonomous rat soleus muscle electrical activity under unloading conditions.

Metformin Pre-Treatment as a Means of Mitigating Disuse-Induced Rat Soleus Muscle Wasting.

Currently, no ideal treatment exists to combat skeletal muscle disuse-induced atrophy and loss of strength. Because the activity of AMP-activated protein kinase (AMPK) in rat soleus muscle is suppressed at the early stages of disuse, we hypothesized that pre-treatment of rats with metformin (an AMPK activator) would exert beneficial effects on skeletal muscle during disuse. Muscle disuse was performed via hindlimb suspension (HS).

AMPK Phosphorylation Impacts Apoptosis in Differentiating Myoblasts Isolated from Atrophied Rat Soleus Muscle.

Regrowth of atrophied myofibers depends on muscle satellite cells (SCs) that exist outside the plasma membrane. Muscle atrophy appears to result in reduced number of SCs due to apoptosis. Given reduced AMP-activated protein kinase (AMPK) activity during differentiation of primary myoblasts derived from atrophic muscle, we hypothesized that there may be a potential link between AMPK and susceptibility of differentiating myoblasts to apoptosis.

Changes in the Mechanical Properties of Fast and Slow Skeletal Muscle after 7 and 21 Days of Restricted Activity in Rats.

Disuse muscle atrophy is usually accompanied by changes in skeletal muscle structure, signaling, and contractile potential. Different models of muscle unloading can provide valuable information, but the protocols of experiments with complete immobilization are not physiologically representative of a sedentary lifestyle, which is highly prevalent among humans now. In the current study, we investigated the potential effects of restricted activity on the mechanical characteristics of rat postural (soleus) and locomotor (extensor digitorum longus, EDL) muscles.

Metformin Attenuates Slow-to-Fast Fiber Shift and Proteolysis Markers Increase in Rat Soleus after 7 Days of Rat Hindlimb Unloading.

Muscle unloading leads to signaling alterations that cause muscle atrophy and weakness. The cellular energy sensor AMPK can regulate myofiber-type shift, calcium-dependent signaling and ubiquitin-proteasome system markers. We hypothesized that the prevention of p-AMPK downregulation during the first week of muscle unloading would impede atrophy development and the slow-to-fast shift of soleus muscle fibers, and the aim of the study was to test this hypothesis.

Inhibition of mTORC1 differentially affects ribosome biogenesis in rat soleus muscle at the early and later stages of hindlimb unloading.

Prolonged inactivity of skeletal muscles due to limb immobilization, bedrest, and exposure to microgravity results in a significant muscle atrophy. Inactivity-induced muscle atrophy is caused by a downregulation of protein synthesis (PS) and increased proteolysis. Mechanistic target of rapamycin complex 1 (mTORC1) is considered to be one of the main regulators of translational capacity (quantity of ribosomes), a key determinant of PS.

Cultured Myoblasts Derived from Rat Soleus Muscle Show Altered Regulation of Proliferation and Myogenesis during the Course of Mechanical Unloading.

The structure and function of soleus muscle fibers undergo substantial remodeling under real or simulated microgravity conditions. However, unloading-induced changes in the functional activity of skeletal muscle primary myoblasts remain poorly studied. The purpose of our study was to investigate how short-term and long-term mechanical unloading would affect cultured myoblasts derived from rat soleus muscle.

Effect of enhanced muscle tone on the expression of atrogenes and cytoskeletal proteins during postural muscle unloading.

Unlabelled: Skeletal muscle unloading leads to the decreased electrical activity and decline of muscle tone.

Aims: Current study evaluated the effect of muscle tone preservation achieved by tetanus toxin (TeNT) treatment on signaling pathways regulating atrophic processes during unloading.

Main Methods: Four groups of rats were used: non-treated control (C), control rats with TeNT administration (CT), 7 days of unloading/hindlimb suspension with placebo (HS), and 7 days of unloading with TeNT administration (HST).

Effects of Various Muscle Disuse States and Countermeasures on Muscle Molecular Signaling.

Skeletal muscle is capable of changing its structural parameters, metabolic rate and functional characteristics within a wide range when adapting to various loading regimens and states of the organism. Prolonged muscle inactivation leads to serious negative consequences that affect the quality of life and work capacity of people. This review examines various conditions that lead to decreased levels of muscle loading and activity and describes the key molecular mechanisms of muscle responses to these conditions.

Prochlorperazine Withdraws the Delayed Onset Tonic Activity of Unloaded Rat Soleus Muscle: A Pilot Study.

A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological significance and mechanisms of such activity of motoneurons under unloading conditions are currently unclear. Since hyperactivity of motoneurons and muscle spasticity after spinal cord injury are associated with KCC2 downregulation, we hypothesized that a decrease in potassium (K)/chloride (Cl) co-transporter 2 (KCC2) in motoneurons would be responsible for an increase in soleus muscle EMG activity during HS.

HDAC4 Is Indispensable for Reduced Slow Myosin Expression at the Early Stage of Hindlimb Unloading in Rat Soleus Muscle.

It is well known that reduced contractile activity of the main postural soleus muscle during long-term bedrest, immobilization, hindlimb unloading, and space flight leads to increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC). The signaling cascade such as HDAC4/MEF2-D pathway is well-known to take part in regulating MyHC I gene expression. Earlier, we found a significant increase of HDAC4 in myonuclei due to AMPK dephosphorylation during 24 h of hindlimb unloading via hindlimb suspension (HU) and it had a significant impact on the expression of MyHC isoforms in rat soleus causing a decrease in MyHC I(β) pre-mRNA and mRNA expression as well as MyHC IIa mRNA expression.

Role of Pannexin 1 ATP-Permeable Channels in the Regulation of Signaling Pathways during Skeletal Muscle Unloading.

Skeletal muscle unloading results in atrophy. We hypothesized that pannexin 1 ATP-permeable channel (PANX1) is involved in the response of muscle to unloading. We tested this hypothesis by blocking PANX1, which regulates efflux of ATP from the cytoplasm.

Plantar Stimulations during 3-Day Hindlimb Unloading Prevent Loss of Neural Progenitors and Maintain ERK1/2 Activity in the Rat Hippocampus.

Adult neurogenesis is a flexible process that depends on the environment and correlates with cognitive functions. Cognitive functions are impaired by various factors including space flight conditions and reduced physical activity. Physically active life significantly improves both cognition and the hippocampal neurogenesis.

The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions.

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual's quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function.

Chronic Ouabain Prevents Na,K-ATPase Dysfunction and Targets AMPK and IL-6 in Disused Rat Soleus Muscle.

Sustained sarcolemma depolarization due to loss of the Na,K-ATPase function is characteristic for skeletal muscle motor dysfunction. Ouabain, a specific ligand of the Na,K-ATPase, has a circulating endogenous analogue. We hypothesized that the Na,K-ATPase targeted by the elevated level of circulating ouabain modulates skeletal muscle electrogenesis and prevents its disuse-induced disturbances.