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  Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans

Monti, E., Reggiani, C., Franchi, M. V., Toniolo, L., Sandri, M., Armani, A., et al. (2021). Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans. The Journal of Physiology - London, 599(12), 3037-3061. doi:10.1113/JP281365.

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 Creators:
Monti, Elena1, Author
Reggiani, Carlo1, Author
Franchi, Martino V.1, Author
Toniolo, Luana1, Author
Sandri, Marco1, Author
Armani, Andrea1, Author
Zampieri, Sandra1, Author
Giacomello, Emiliana1, Author
Sarto, Fabio1, Author
Sirago, Giuseppe1, Author
Murgia, Marta2, Author           
Nogara, Leonardo1, Author
Marcucci, Lorenzo1, Author
Ciciliot, Stefano1, Author
Simunic, Bostjan1, Author
Pisot, Rado1, Author
Narici, Marco V.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: HUMAN SKELETAL-MUSCLE; COOMASSIE BRILLIANT BLUE; TERMINAL AGRIN FRAGMENT; MAXIMAL EXPLOSIVE POWER; SARCOPLASMIC-RETICULUM; BED-REST; PROTEIN-SYNTHESIS; N-CAM; CONTRACTILE PROPERTIES; MECHANICAL-PROPERTIESNeurosciences & Neurology; Physiology; Ca2+ dynamics; muscle atrophy; NCAM; neuromuscular junction instability; sarcoplasmic reticulum; single fibre atrophy; single fibre contractile impairment; unloading;
 Abstract: Key points
Few days of unloading are sufficient to induce a decline of skeletal muscle mass and function; notably, contractile force is lost at a faster rate than muscle mass.
The reasons behind this disproportionate loss of muscle force are still poorly understood.
We provide strong evidence of two mechanisms only hypothesized until now for the rapid muscle force loss in only 10 days of bed rest.
Our results show that an initial neuromuscular junction instability, accompanied by alterations in the innervation status and impairment of single fibre sarcoplasmic reticulum function contribute to the loss of contractile force in front of a preserved myofibrillar function and central activation capacity.
Early onset of neuromuscular junction instability and impairment in calcium dynamics involved in excitation-contraction coupling are proposed as eligible determinants to the greater decline in muscle force than in muscle size during unloading.
Unloading induces rapid skeletal muscle atrophy and functional decline. Importantly, force is lost at a much higher rate than muscle mass. We aimed to investigate the early determinants of the disproportionate loss of force compared to that of muscle mass in response to unloading. Ten young participants underwent 10 days of bed rest (BR). At baseline (BR0) and at 10 days (BR10), quadriceps femoris (QF) volume (VOL) and isometric maximum voluntary contraction (MVC) were assessed. At BR0 and BR10 blood samples and biopsies of vastus lateralis (VL) muscle were collected. Neuromuscular junction (NMJ) stability and myofibre innervation status were assessed, together with single fibre mechanical properties and sarcoplasmic reticulum (SR) calcium handling. From BR0 to BR10, QFVOL and MVC decreased by 5.2% (P = 0.003) and 14.3% (P < 0.001), respectively. Initial and partial denervation was detected from increased neural cell adhesion molecule (NCAM)-positive myofibres at BR10 compared with BR0 (+3.4%, P = 0.016). NMJ instability was further inferred from increased C-terminal agrin fragment concentration in serum (+19.2% at BR10, P = 0.031). Fast fibre cross-sectional area (CSA) showed a trend to decrease by 15% (P = 0.055) at BR10, while single fibre maximal tension (force/CSA) was unchanged. However, at BR10 SR Ca2+ release in response to caffeine decreased by 35.1% (P < 0.002) and 30.2% (P < 0.001) in fast and slow fibres, respectively, pointing to an impaired excitation-contraction coupling. These findings support the view that the early onset of NMJ instability and impairment in SR function are eligible mechanisms contributing to the greater decline in muscle force than in muscle size during unloading.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published online
 Pages: 25
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000652060700001
DOI: 10.1113/JP281365
 Degree: -

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Title: The Journal of Physiology - London
Source Genre: Journal
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Publ. Info: London : Cambridge University Press
Pages: - Volume / Issue: 599 (12) Sequence Number: - Start / End Page: 3037 - 3061 Identifier: ISSN: 0022-3751
CoNE: https://pure.mpg.de/cone/journals/resource/954925334693_2