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Skeletal Muscle Molecular Signalling in Various Models of Disuse and Unloading

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (27 May 2022) | Viewed by 20996

Special Issue Editors


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Guest Editor
Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia
Interests: skeletal muscle; intracellular signaling pathways; skeletal muscle mechanosensory molecules; skeletal muscle atrophy; microgravity; gravitational unloading; muscle disuse; mechanical characteristics; muscle tone; muscle stiffness; passive tension
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Guest Editor
Department of Biomedical Sciences, University of Padova, Via Marzolo 3, 35131 Padova, Italy
Interests: muscle physiology and pathophysiology; intracellular calcium dynamics; myosin isoforms and chemo-mechanical transduction; response to resistance training; adaptation to disuse; muscle function decline with aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the 21st century, mankind is challenged by physical inactivity. In a fast progression through the 20th century, the use of cars, motorbikes, and other motorized vehicles has replaced walking and cycling for most human beings as the production in the fields and in the factories has become mainly reliant on the use of machines. This has reduced the fatiguing aspects of everyday life but at the same time has reshaped lifestyles to be more sedentary. In addition, several people experience a virtually complete motor inactivity due to locomotor restraints; limb and spinal injuries associated with sports, professional, and traffic accidents; long-duration marine and space missions; clinical bed rest. Complete or partial skeletal muscle disuse is the usual consequence of such inactivity.

Skeletal muscle disuse is followed by four basic events: muscle atrophy (loss of muscle mass), muscle atonia (drop of muscle tone/stiffness), slow-to-fast myosin transition, and mitochondria remodeling. These events result in impaired posture and locomotion and dramatic decrease of physical performance. All these events are based upon altered intra- and intercellular skeletal muscle molecular signaling networks which have been under study for the last two decades. In spite of this wealth of studies, we cannot imagine an uncontroversial picture of muscle molecular remodeling under disuse conditions. Thus, it is mandatory to collect the present results and considerations. IJMS announces the Special Issue “Skeletal Muscle Molecular Signalling in Various Models of Disuse and Unloading.” The journal will accept research and review articles covering:

  • Various forms of disuse (extreme sedentary life style, denervation, cast immobilization, spinal transection and isolation, bed rest, dry immersion, hindlimb unloading, space flight, tenotomy, confinement and others);
  • Molecular intracellular and intercellular signaling pathways controlling proteostasis, regulation of gene expression (including myosin phenotype), adaptation of cytoskeletal proteins, changes in mitochondrial structure and function
  • Postural, locomotor and other skeletal muscles
  • Experimental studies with various animal species and humans
  • Countermeasures preventing functional impairment

Prof. Dr. Boris S. Shenkman
Prof. Dr. Carlo Reggiani
Guest Editors

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Keywords

  • skeletal muscle
  • disuse
  • unloading
  • inactivity
  • muscle atrophy
  • muscle atonia
  • slow-to-fast myosin transition
  • mitochondrial impairment
  • intracellular and intercellular signal transduction pathways
  • proteostasis
  • cytoskeleton
  • gene expression

Published Papers (6 papers)

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Research

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17 pages, 2145 KiB  
Article
Exercise Preconditioning Blunts Early Atrogenes Expression and Atrophy in Gastrocnemius Muscle of Hindlimb Unloaded Mice
by Lorenza Brocca, Maira Rossi, Monica Canepari, Roberto Bottinelli and Maria Antonietta Pellegrino
Int. J. Mol. Sci. 2022, 23(1), 148; https://doi.org/10.3390/ijms23010148 - 23 Dec 2021
Cited by 6 | Viewed by 2966
Abstract
A large set of FoxOs-dependent genes play a primary role in controlling muscle mass during hindlimb unloading. Mitochondrial dysfunction can modulate such a process. We hypothesized that endurance exercise before disuse can protect against disuse-induced muscle atrophy by enhancing peroxisome proliferator-activated receptor-γ coactivator-1α [...] Read more.
A large set of FoxOs-dependent genes play a primary role in controlling muscle mass during hindlimb unloading. Mitochondrial dysfunction can modulate such a process. We hypothesized that endurance exercise before disuse can protect against disuse-induced muscle atrophy by enhancing peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) expression and preventing mitochondrial dysfunction and energy-sensing AMP-activated protein kinase (AMPK) activation. We studied cross sectional area (CSA) of muscle fibers of gastrocnemius muscle by histochemistry following 1, 3, 7, and 14 days of hindlimb unloading (HU). We used Western blotting and qRT-PCR to study mitochondrial dynamics and FoxOs-dependent atrogenes’ expression at 1 and 3 days after HU. Preconditioned animals were submitted to moderate treadmill exercise for 7 days before disuse. Exercise preconditioning protected the gastrocnemius from disuse atrophy until 7 days of HU. It blunted alterations in mitochondrial dynamics up to 3 days after HU and the expression of most atrogenes at 1 day after disuse. In preconditioned mice, the activation of atrogenes resumed 3 days after HU when mitochondrial dynamics, assessed by profusion and pro-fission markers (mitofusin 1, MFN1, mitofusin 2, MFN2, optic atrophy 1, OPA1, dynamin related protein 1, DRP1 and fission 1, FIS1), PGC1α levels, and AMPK activation were at a basal level. Therefore, the normalization of mitochondrial dynamics and function was not sufficient to prevent atrogenes activation just a few days after HU. The time course of sirtuin 1 (SIRT1) expression and content paralleled the time course of atrogenes’ expression. In conclusion, seven days of endurance exercise counteracted alterations of mitochondrial dynamics and the activation of atrogenes early into disuse. Despite the normalization of mitochondrial dynamics, the effect on atrogenes’ suppression died away within 3 days of HU. Interestingly, muscle protection lasted until 7 days of HU. A longer or more intense exercise preconditioning may prolong atrogenes suppression and muscle protection. Full article
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19 pages, 5320 KiB  
Article
Early Deconditioning of Human Skeletal Muscles and the Effects of a Thigh Cuff Countermeasure
by Théo Fovet, Corentin Guilhot, Laurence Stevens, Valérie Montel, Pierre Delobel, Rémi Roumanille, Michel-Yves Semporé, Damien Freyssenet, Guillaume Py, Thomas Brioche and Angèle Chopard
Int. J. Mol. Sci. 2021, 22(21), 12064; https://doi.org/10.3390/ijms222112064 - 8 Nov 2021
Cited by 7 | Viewed by 2646
Abstract
Muscle deconditioning is a major consequence of a wide range of conditions from spaceflight to a sedentary lifestyle, and occurs as a result of muscle inactivity, leading to a rapid decrease in muscle strength, mass, and oxidative capacity. The early changes that appear [...] Read more.
Muscle deconditioning is a major consequence of a wide range of conditions from spaceflight to a sedentary lifestyle, and occurs as a result of muscle inactivity, leading to a rapid decrease in muscle strength, mass, and oxidative capacity. The early changes that appear in the first days of inactivity must be studied to determine effective methods for the prevention of muscle deconditioning. To evaluate the mechanisms of muscle early changes and the vascular effect of a thigh cuff, a five-day dry immersion (DI) experiment was conducted by the French Space Agency at the MEDES Space Clinic (Rangueil, Toulouse). Eighteen healthy males were recruited and divided into a control group and a thigh cuff group, who wore a thigh cuff at 30 mmHg. All participants underwent five days of DI. Prior to and at the end of the DI, the lower limb maximal strength was measured and muscle biopsies were collected from the vastus lateralis muscle. Five days of DI resulted in muscle deconditioning in both groups. The maximal voluntary isometric contraction of knee extension decreased significantly. The muscle fiber cross-sectional area decreased significantly by 21.8%, and the protein balance seems to be impaired, as shown by the reduced activation of the mTOR pathway. Measurements of skinned muscle fibers supported these results and potential changes in oxidative capacity were highlighted by a decrease in PGC1-α levels. The use of the thigh cuff did not prevent muscle deconditioning or impact muscle function. These results suggest that the major effects of muscle deconditioning occur during the first few days of inactivity, and countermeasures against muscle deconditioning should target this time period. These results are also relevant for the understanding of muscle weakness induced by muscle diseases, aging, and patients in intensive care. Full article
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13 pages, 1211 KiB  
Article
Characterizing SERCA Function in Murine Skeletal Muscles after 35–37 Days of Spaceflight
by Jessica L. Braun, Mia S. Geromella, Sophie I. Hamstra, Holt N. Messner and Val A. Fajardo
Int. J. Mol. Sci. 2021, 22(21), 11764; https://doi.org/10.3390/ijms222111764 - 29 Oct 2021
Cited by 11 | Viewed by 3033
Abstract
It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Although the [...] Read more.
It is well established that microgravity exposure causes significant muscle weakness and atrophy via muscle unloading. On Earth, muscle unloading leads to a disproportionate loss in muscle force and size with the loss in muscle force occurring at a faster rate. Although the exact mechanisms are unknown, a role for Ca2+ dysregulation has been suggested. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump actively brings cytosolic Ca2+ into the SR, eliciting muscle relaxation and maintaining low intracellular Ca2+ ([Ca2+]i). SERCA dysfunction contributes to elevations in [Ca2+]i, leading to cellular damage, and may contribute to the muscle weakness and atrophy observed with spaceflight. Here, we investigated SERCA function, SERCA regulatory protein content, and reactive oxygen/nitrogen species (RONS) protein adduction in murine skeletal muscle after 35–37 days of spaceflight. In male and female soleus muscles, spaceflight led to drastic impairments in Ca2+ uptake despite significant increases in SERCA1a protein content. We attribute this impairment to an increase in RONS production and elevated total protein tyrosine (T) nitration and cysteine (S) nitrosylation. Contrarily, in the tibialis anterior (TA), we observed an enhancement in Ca2+ uptake, which we attribute to a shift towards a faster muscle fiber type (i.e., increased myosin heavy chain IIb and SERCA1a) without elevated total protein T-nitration and S-nitrosylation. Thus, spaceflight affects SERCA function differently between the soleus and TA. Full article
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14 pages, 1748 KiB  
Article
Role of Pannexin 1 ATP-Permeable Channels in the Regulation of Signaling Pathways during Skeletal Muscle Unloading
by Ksenia A. Zaripova, Ekaterina P. Kalashnikova, Svetlana P. Belova, Tatiana Y. Kostrominova, Boris S. Shenkman and Tatiana L. Nemirovskaya
Int. J. Mol. Sci. 2021, 22(19), 10444; https://doi.org/10.3390/ijms221910444 - 28 Sep 2021
Cited by 15 | Viewed by 2246
Abstract
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. Rats were divided into six [...] Read more.
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. Rats were divided into six groups (eight rats each): non-treated control for 1 and 3 days of the experiments (1C and 3C, respectively), 1 and 3 days of hindlimb suspension (HS) with placebo (1H and 3H, respectively), and 1 and 3 days of HS with PANX1 inhibitor probenecid (PRB; 1HP and 3HP, respectively). When compared with 3C group there was a significant increase in ATP in soleus muscle of 3H and 3HP groups (32 and 51%, respectively, p < 0.05). When compared with 3H group, 3HP group had: (1) lower mRNA expression of E3 ligases MuRF1 and MAFbx (by 50 and 38% respectively, p < 0.05) and MYOG (by 34%, p < 0.05); (2) higher phosphorylation of p70S6k and p90RSK (by 51 and 35% respectively, p < 0.05); (3) lower levels of phosphorylated eEF2 (by 157%, p < 0.05); (4) higher level of phosphorylated GSK3β (by 189%, p < 0.05). In conclusion, PANX1 ATP-permeable channels are involved in the regulation of muscle atrophic processes by modulating expression of E3 ligases, and protein translation and elongation processes during unloading. Full article
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Review

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14 pages, 582 KiB  
Review
Roles of ATP and SERCA in the Regulation of Calcium Turnover in Unloaded Skeletal Muscles: Current View and Future Directions
by Tatiana L. Nemirovskaya and Kristina A. Sharlo
Int. J. Mol. Sci. 2022, 23(13), 6937; https://doi.org/10.3390/ijms23136937 - 22 Jun 2022
Cited by 11 | Viewed by 2711
Abstract
A decrease in skeletal muscle contractile activity or its complete cessation (muscle unloading or disuse) leads to muscle fibers’ atrophy and to alterations in muscle performance. These changes negatively affect the quality of life of people who, for one reason or another, are [...] Read more.
A decrease in skeletal muscle contractile activity or its complete cessation (muscle unloading or disuse) leads to muscle fibers’ atrophy and to alterations in muscle performance. These changes negatively affect the quality of life of people who, for one reason or another, are forced to face a limitation of physical activity. One of the key regulatory events leading to the muscle disuse-induced changes is an impairment of calcium homeostasis, which leads to the excessive accumulation of calcium ions in the sarcoplasm. This review aimed to analyze the triggering mechanisms of calcium homeostasis impairment (including those associated with the accumulation of high-energy phosphates) under various types of muscle unloading. Here we proposed a hypothesis about the regulatory mechanisms of SERCA and IP3 receptors activity during muscle unloading, and about the contribution of these mechanisms to the excessive calcium ion myoplasmic accumulation and gene transcription regulation via excitation–transcription coupling. Full article
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35 pages, 1686 KiB  
Review
Effects of Various Muscle Disuse States and Countermeasures on Muscle Molecular Signaling
by Kristina Sharlo, Sergey A. Tyganov, Elena Tomilovskaya, Daniil V. Popov, Alina A. Saveko and Boris S. Shenkman
Int. J. Mol. Sci. 2022, 23(1), 468; https://doi.org/10.3390/ijms23010468 - 31 Dec 2021
Cited by 16 | Viewed by 6462
Abstract
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 [...] Read more.
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. It also details the theoretical foundations of various methods preventing adverse muscle changes caused by decreased motor activity and describes these methods. A number of recent studies presented in this review make it possible to determine the molecular basis of the countermeasure methods used in rehabilitation and space medicine for many years, as well as to identify promising new approaches to rehabilitation and to form a holistic understanding of the mechanisms of gravity force control over the muscular system. Full article
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