Cargando…
Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans
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 tw...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359852/ https://www.ncbi.nlm.nih.gov/pubmed/33881176 http://dx.doi.org/10.1113/JP281365 |
_version_ | 1783737622329294848 |
---|---|
author | Monti, Elena Reggiani, Carlo Franchi, Martino V. Toniolo, Luana Sandri, Marco Armani, Andrea Zampieri, Sandra Giacomello, Emiliana Sarto, Fabio Sirago, Giuseppe Murgia, Marta Nogara, Leonardo Marcucci, Lorenzo Ciciliot, Stefano Šimunic, Boštjan Pišot, Rado Narici, Marco V. |
author_facet | Monti, Elena Reggiani, Carlo Franchi, Martino V. Toniolo, Luana Sandri, Marco Armani, Andrea Zampieri, Sandra Giacomello, Emiliana Sarto, Fabio Sirago, Giuseppe Murgia, Marta Nogara, Leonardo Marcucci, Lorenzo Ciciliot, Stefano Šimunic, Boštjan Pišot, Rado Narici, Marco V. |
author_sort | Monti, Elena |
collection | PubMed |
description | 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. ABSTRACT: 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-8359852 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83598522021-08-17 Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans Monti, Elena Reggiani, Carlo Franchi, Martino V. Toniolo, Luana Sandri, Marco Armani, Andrea Zampieri, Sandra Giacomello, Emiliana Sarto, Fabio Sirago, Giuseppe Murgia, Marta Nogara, Leonardo Marcucci, Lorenzo Ciciliot, Stefano Šimunic, Boštjan Pišot, Rado Narici, Marco V. J Physiol Muscle 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. ABSTRACT: 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 Ca(2+) 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. John Wiley and Sons Inc. 2021-05-19 2021-06-15 /pmc/articles/PMC8359852/ /pubmed/33881176 http://dx.doi.org/10.1113/JP281365 Text en © 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Muscle Monti, Elena Reggiani, Carlo Franchi, Martino V. Toniolo, Luana Sandri, Marco Armani, Andrea Zampieri, Sandra Giacomello, Emiliana Sarto, Fabio Sirago, Giuseppe Murgia, Marta Nogara, Leonardo Marcucci, Lorenzo Ciciliot, Stefano Šimunic, Boštjan Pišot, Rado Narici, Marco V. Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title | Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title_full | Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title_fullStr | Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title_full_unstemmed | Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title_short | Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
title_sort | neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans |
topic | Muscle |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359852/ https://www.ncbi.nlm.nih.gov/pubmed/33881176 http://dx.doi.org/10.1113/JP281365 |
work_keys_str_mv | AT montielena neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT reggianicarlo neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT franchimartinov neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT toniololuana neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT sandrimarco neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT armaniandrea neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT zampierisandra neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT giacomelloemiliana neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT sartofabio neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT siragogiuseppe neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT murgiamarta neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT nogaraleonardo neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT marcuccilorenzo neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT ciciliotstefano neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT simunicbostjan neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT pisotrado neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans AT naricimarcov neuromuscularjunctioninstabilityandalteredintracellularcalciumhandlingasearlydeterminantsofforcelossduringunloadinginhumans |