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Precontractile optical response during excitation-contraction in human muscle revealed by non-invasive high-speed spatiotemporal NIR measurement.

ABSTRACT: During muscle contraction the excitation-contraction process mediates the neural input and mechanical output. Proper muscle function and body locomotion depends on the status of the elements in the same process. However, non-invasive and in-vivo methods to study this are not available. Here we show the existence of an optical response occurring during the excitation-contraction process in human biceps brachii muscle. We developed a non-invasive instrument from a photodiode array and light emitting diodes to detect spatially propagating (~5?m/s) and precontractile (~6 ms onset) optical signals closely related to the action potential during electrostimulation. Although this phenomenon was observed 60 years ago on isolated frog muscle cells in the lab, it has not been shown in-vivo before now. We anticipate our results to be a starting point for a new category in-vivo studies, characterising alterations in the excitation-contraction process in patients with neuromuscular disease and to monitor effects of therapy.

SUBMITTER: Lindkvist M

PROVIDER: S-EPMC5760718 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Precontractile optical response during excitation-contraction in human muscle revealed by non-invasive high-speed spatiotemporal NIR measurement.

Lindkvist Markus M Granåsen Gabriel G Grönlund Christer C

Scientific reports 20180109 1

During muscle contraction the excitation-contraction process mediates the neural input and mechanical output. Proper muscle function and body locomotion depends on the status of the elements in the same process. However, non-invasive and in-vivo methods to study this are not available. Here we show the existence of an optical response occurring during the excitation-contraction process in human biceps brachii muscle. We developed a non-invasive instrument from a photodiode array and light emitti ...[more]

PMID: 29317688

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Project description:In skeletal muscle, excitation-contraction (EC) coupling requires depolarization-induced conformational rearrangements in L-type Ca(2+) channel (Ca(V)1.1) to be communicated to the type 1 ryanodine-sensitive Ca(2+) release channel (RYR1) of the sarcoplasmic reticulum (SR) via transient protein-protein interactions. Although the molecular mechanism that underlies conformational coupling between Ca(V)1.1 and RYR1 has been investigated intensely for more than 25 years, the question of whether such signaling occurs via a direct interaction between the principal, voltage-sensing ?(1S) subunit of Ca(V)1.1 and RYR1 or through an intermediary protein persists. A substantial body of evidence supports the idea that the auxiliary ?(1a) subunit of Ca(V)1.1 is a conduit for this intermolecular communication. However, a direct role for ?(1a) has been difficult to test because ?(1a) serves two other functions that are prerequisite for conformational coupling between Ca(V)1.1 and RYR1. Specifically, ?(1a) promotes efficient membrane expression of Ca(V)1.1 and facilitates the tetradic ultrastructural arrangement of Ca(V)1.1 channels within plasma membrane-SR junctions. In this paper, we demonstrate that overexpression of the RGK protein Rem, an established ? subunit-interacting protein, in adult mouse flexor digitorum brevis fibers markedly reduces voltage-induced myoplasmic Ca(2+) transients without greatly affecting Ca(V)1.1 targeting, intramembrane gating charge movement, or releasable SR Ca(2+) store content. In contrast, a ?(1a)-binding-deficient Rem triple mutant (R200A/L227A/H229A) has little effect on myoplasmic Ca(2+) release in response to membrane depolarization. Thus, Rem effectively uncouples the voltage sensors of Ca(V)1.1 from RYR1-mediated SR Ca(2+) release via its ability to interact with ?(1a). Our findings reveal Rem-expressing adult muscle as an experimental system that may prove useful in the definition of the precise role of the ?(1a) subunit in skeletal-type EC coupling.

Project description:BackgroundWe have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1-/- mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age-matched adult (8-10 months) wild-type (WT) and Sod1-/- mice in comparison with old (25-28 months) WT mice.MethodsIn vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump was measured using an NADH-linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real-time reverse transcription PCR was used to measure gene expression.ResultsThe specific force generated by the extensor digitorum longus muscle was reduced in the Sod1-/- and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (≈14%) and adult Sod1-/- (≈33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor α1 and SERCA2 were significantly elevated (≈45% and ≈57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (≈21%) in Sod1-/- mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.ConclusionsOur data suggest that the muscle weakness in Sod1-/- and old WT mice is in part driven by reactive oxygen species-mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.

Dataset Information

Precontractile optical response during excitation-contraction in human muscle revealed by non-invasive high-speed spatiotemporal NIR measurement.

Publications

Precontractile optical response during excitation-contraction in human muscle revealed by non-invasive high-speed spatiotemporal NIR measurement.

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