Dataset Information

Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.

ABSTRACT: The protease ?-secretase 1 (Bace1) was identified through its critical role in production of amyloid-? peptides (A?), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing ?1 Nrg1 (IgNrg1?1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism.

SUBMITTER: Cheret C

PROVIDER: S-EPMC3715864 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.

Cheret Cyril C Willem Michael M Fricker Florence R FR Wende Hagen H Wulf-Goldenberg Annika A Tahirovic Sabina S Nave Klaus-Armin KA Saftig Paul P Haass Christian C Garratt Alistair N AN Bennett David L DL Birchmeier Carmen C

The EMBO journal 20130621 14

The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing β1 Nrg1 (IgNrg1β1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo result ...[more]

PMID: 23792428

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Project description:Muscle spindle proprioceptive receptors play a primary role in encoding the effects of external mechanical perturbations to the body. During externally-imposed stretches of passive, i.e. electrically-quiescent, muscles, the instantaneous firing rates (IFRs) of muscle spindles are associated with characteristics of stretch such as length and velocity. However, even in passive muscle, there are history-dependent transients of muscle spindle firing that are not uniquely related to muscle length and velocity, nor reproduced by current muscle spindle models. These include acceleration-dependent initial bursts, increased dynamic response to stretch velocity if a muscle has been isometric, and rate relaxation, i.e., a decrease in tonic IFR when a muscle is held at a constant length after being stretched. We collected muscle spindle spike trains across a variety of muscle stretch kinematic conditions, including systematic changes in peak length, velocity, and acceleration. We demonstrate that muscle spindle primary afferents in passive muscle fire in direct relationship to muscle force-related variables, rather than length-related variables. Linear combinations of whole muscle-tendon force and the first time derivative of force (dF/dt) predict the entire time course of transient IFRs in muscle spindle Ia afferents during stretch (i.e., lengthening) of passive muscle, including the initial burst, the dynamic response to lengthening, and rate relaxation following lengthening. Similar to acceleration scaling found previously in postural responses to perturbations, initial burst amplitude scaled equally well to initial stretch acceleration or dF/dt, though later transients were only described by dF/dt. The transient increase in dF/dt at the onset of lengthening reflects muscle short-range stiffness due to cross-bridge dynamics. Our work demonstrates a critical role of muscle cross-bridge dynamics in history-dependent muscle spindle IFRs in passive muscle lengthening conditions relevant to the detection and sensorimotor response to mechanical perturbations to the body, and to previously-described history-dependence in perception of limb position.

Dataset Information

Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.

Publications

Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles.

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