Molecular correlates of muscle spindle and Golgi tendon organ afferents

AbstractProprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output.

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Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis

10.1101/2020.04.03.023986 ◽

2020 ◽

Cited By ~ 2

Author(s):

Katherine M. Oliver ◽

Danny M. Florez-Paz ◽

Tudor C. Badea ◽

George Z. Mentis ◽

Vilas Menon ◽

...

Keyword(s):

Muscle Spindle ◽

Developmental Stages ◽

Motor Behavior ◽

Molecular Signature ◽

Golgi Tendon Organ ◽

Sensory Afferents ◽

Electrophysiological Recordings ◽

Muscle Afferent ◽

Tendon Organ

AbstractAnatomical and physiological analyses have long revealed differences between proprioceptive groups Ia, II, and Ib sensory neurons, yet the molecular correlates of these three muscle afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and, using unbiased bioinformatics approaches, detected five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia (DRG) and skeletal muscle provides evidence these clusters correspond to functionally distinct muscle spindle (MS) or Golgi tendon organ (GTO) afferent proprioceptors. Remarkably, while we uncovered just one type of GTO afferents, four of the five clusters represent MS afferents, thus demonstrating a previously unappreciated diversity among these muscle proprioceptors. In vitro electrophysiological recordings reveal just two broadly distinct proprioceptor types, and suggest that the refinement of functional subtype diversity may occur along multiple axes of maturation. Lineage analysis between proprioceptor transcriptomes at different developmental stages show little or no correlation for transcripts that define adult MS or GTO afferents, supporting the idea that proprioceptor subtype identity emerges late in development. Together, our data provide the first comprehensive molecular signature for groups Ia and II MS afferents and group Ib GTO afferents, and offer new strategies for genetic interrogation of the role of these individual proprioceptor subtypes in regulating voluntary motor behavior.

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Direct contribution of skeletal muscle mesenchymal progenitors to bone repair

Nature Communications ◽

10.1038/s41467-021-22842-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anais Julien ◽

Anuya Kanagalingam ◽

Ester Martínez-Sarrà ◽

Jérome Megret ◽

Marine Luka ◽

...

Keyword(s):

Skeletal Muscle ◽

Bone Healing ◽

Bone Repair ◽

Fibrotic Response ◽

Mesenchymal Progenitors ◽

Fibrotic Tissue ◽

Bone Injury ◽

Single Cell Rna Sequencing ◽

Musculoskeletal Trauma

AbstractBone regenerates by activation of tissue resident stem/progenitor cells, formation of a fibrous callus followed by deposition of cartilage and bone matrices. Here, we show that mesenchymal progenitors residing in skeletal muscle adjacent to bone mediate the initial fibrotic response to bone injury and also participate in cartilage and bone formation. Combined lineage and single-cell RNA sequencing analyses reveal that skeletal muscle mesenchymal progenitors adopt a fibrogenic fate before they engage in chondrogenesis after fracture. In polytrauma, where bone and skeletal muscle are injured, skeletal muscle mesenchymal progenitors exhibit altered fibrogenesis and chondrogenesis. This leads to impaired bone healing, which is due to accumulation of fibrotic tissue originating from skeletal muscle and can be corrected by the anti-fibrotic agent Imatinib. These results elucidate the central role of skeletal muscle in bone regeneration and provide evidence that skeletal muscle can be targeted to prevent persistent callus fibrosis and improve bone healing after musculoskeletal trauma.

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Regulating muscle spindle and Golgi tendon organ proprioceptor phenotypes

Current Opinion in Physiology ◽

10.1016/j.cophys.2020.11.001 ◽

2021 ◽

Vol 19 ◽

pp. 204-210

Author(s):

Niccolò Zampieri ◽

Joriene C de Nooij

Keyword(s):

Muscle Spindle ◽

Golgi Tendon Organ ◽

Tendon Organ

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Force Coding by Populations of Cat Golgi Tendon Organ afferents: The Role of Muscle Length and Motor Unit Pool Activation Strategies

Alpha and Gamma Motor Systems ◽

10.1007/978-1-4615-1935-5_64 ◽

1995 ◽

pp. 302-308 ◽

Cited By ~ 3

Author(s):

M. Hulliger ◽

P. Sjölander ◽

U. R. Windhorst ◽

E. Otten

Keyword(s):

Motor Unit ◽

Muscle Length ◽

Golgi Tendon Organ ◽

Tendon Organ

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Classification of human muscle stretch receptor afferents: a Bayesian approach

Journal of Neurophysiology ◽

10.1152/jn.1990.63.6.1314 ◽

1990 ◽

Vol 63 (6) ◽

pp. 1314-1322 ◽

Cited By ~ 49

Author(s):

B. B. Edin ◽

A. B. Vallbo

Keyword(s):

Muscle Spindle ◽

Small Amplitude ◽

Discharge Rate ◽

Muscle Afferents ◽

Human Muscle ◽

Golgi Tendon Organ ◽

Bayesian Decision ◽

Prior Probabilities ◽

Tendon Organ

1. A sample of 124 human muscle afferents originating from the finger extensor muscles were recorded from the radial nerve in the upper arm. A method is described to formalize the classification of units in muscle spindle primary and secondary afferents and Golgi tendon organ afferents on the basis of a few, nonrigorous assumptions. The classification was based on experimental data that largely have been described in a series of previous papers, although some additional data were collected in the present study. 2. The units were subjected to five tests providing identification data: twitch contraction test, ramp-and-hold stretch, small-amplitude sinusoidal stretches superimposed on ramp stretch, stretch sensitization, and isometric contraction/relaxation. From these five tests the following eight response features were extracted: response to maximal isometric twitch contractions, type of stretch sensitization, correlation between discharge rate and contractile force, response to sudden isometric relaxation, presence or absence of an initial burst, deceleration response, prompt silencing at slow muscle shortening, and driving by small-amplitude sinusoidal stretches. 3. A Bayesian decision procedure was adopted to classify the units on the basis of the eight discriminators. As a first step, units were provisionally classified into muscle spindle primary and secondary afferents, and Golgi tendon organ afferents, by intuitively weighting their responses to the identification tests. Prior probabilities were estimated on the basis of the provisional classification. The eight response features were analyzed and tabulated for all afferents, and the likelihood functions of the tests were directly calculated on the basis of these data.(ABSTRACT TRUNCATED AT 250 WORDS)

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Muscle afferent responses to isometric contractions and relaxations in humans

Journal of Neurophysiology ◽

10.1152/jn.1990.63.6.1307 ◽

1990 ◽

Vol 63 (6) ◽

pp. 1307-1313 ◽

Cited By ~ 96

Author(s):

B. B. Edin ◽

A. B. Vallbo

Keyword(s):

Muscle Spindle ◽

Isometric Contraction ◽

Discharge Rate ◽

Golgi Tendon Organ ◽

Muscle Spindle Afferents ◽

Golgi Tendon Organs ◽

Relaxation Phase ◽

Isometric Twitch ◽

The Individual ◽

Tendon Organ

1. One hundred and two single afferents from the finger extensor muscles of humans were studied with the microneurography technique. 2. The afferents were provisionally classified as primary muscle spindle afferents (62/102), secondary spindle afferents (22), and Golgi tendon organ afferents (18) on the basis of their responses to four tests: 1) ramp-and-hold stretch, 2) 20- and 50-Hz small-amplitude sinusoidal stretch superimposed on ramp-and-hold stretch, 3) maximal isometric twitch contraction, and 4) stretch sensitization. 3. The response profiles of the three unit types were analyzed during slowly rising isometric contraction terminating with an abrupt relaxation. About 75% (61/84) of all muscle spindle afferents increased their discharge during isometric contraction, whereas the discharge was reduced for the remaining afferents. All Golgi tendon organs increased their discharge during the contraction. 4. The level of extrafusal contraction at which a spindle afferent increased its discharge rate often varied from trial to trial, speaking against a fixed fusimotor recruitment level of the individual spindle ending. 5. In 70% of the spindle afferents, a distinct burst of impulses appeared when the subject rapidly relaxed after the isometric contraction. The burst was more common and usually much more prominent with primary than secondary afferents, often reaching instantaneous discharge rates well above 100 Hz. 6. Whereas all Golgi tendon organ afferents displayed an increased discharge during the contraction phase, only one of them exhibited a rate acceleration close to the relaxation phase. However, this response could clearly be identified as being of different nature than the spindle bursts.(ABSTRACT TRUNCATED AT 250 WORDS)

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Dynamic response of human muscle spindle afferents to stretch

Journal of Neurophysiology ◽

10.1152/jn.1990.63.6.1297 ◽

1990 ◽

Vol 63 (6) ◽

pp. 1297-1306 ◽

Cited By ~ 114

Author(s):

B. B. Edin ◽

A. B. Vallbo

Keyword(s):

Dynamic Response ◽

Muscle Spindle ◽

Human Subjects ◽

Muscle Afferents ◽

Human Muscle ◽

Golgi Tendon Organ ◽

Muscle Spindle Afferents ◽

Partial Data ◽

Extensor Muscles ◽

Tendon Organ

1. One hundred and twenty-four muscle afferents from the finger extensor muscles were recorded from the radial nerve in human subjects. 2. The afferents were provisionally classified as muscle spindle primary (78/124) and secondary afferents (25/124), and Golgi tendon organ afferents (21/124), on the basis of their response to 1) maximal twitch contractions, 2) 20- and 50-Hz sinusoids superimposed on ramp-and-hold stretches, 3) stretch sensitization, and 4) isometric contractions and sudden relaxations. 3. Ramp-and-hold stretches at two velocities, 10 and 50 degrees/s, were applied to the appropriate metacarpophalangeal (MCP) joint while the parent muscle remained relaxed. For each unit three discrete parameters were assessed: the presence or absence of 1) an initial burst at the commencement of the ramp stretch, 2) a deceleration response at the beginning of the hold phase, and 3) a prompt silencing at muscle shortening. In addition, two kinds of dynamic indexes were calculated for 79 of the muscle spindle afferents. 4. Most spindle afferents responded readily to stretch, whereas the Golgi tendon organ afferents produced very poor stretch responses. All of them lacked a static response, whereas the dynamic response, when present at all, consisted of only a few impulses. 5. The dynamic index was higher for spindle primaries than for secondaries, and this difference was statistically significant although the distribution was unimodal for spindle afferents as a group. Hence, this parameter was a poor discriminator. 6. Initial bursts, deceleration responses, and silences during imposed shortening were more common in spindle primaries than in secondaries. The differences were significant in all these respects. 7. The three discrete parameters were statistically pairwise independent for the spindle afferents, justifying the combination of the three into a useful battery for discrimination between primary and secondary spindle afferents and the use of this battery as a partial data base for a probability approach towards a solid classification of human muscle afferents.

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