Degeneration of muscle spindles in a murine model of Pompe disease

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Апрель 21, 2023

Abstract Pompe disease is a debilitating medical condition caused by functional deficiency of lysosomal acid alpha-glucosidase (GAA). In addition to muscle weakness, people living with experience motor coordination deficits including an instable gait and posture. We reasoned that impaired spindle function might contribute these deficiencies therefore analyzed proprioception as well structure in 4- 8-month-old Gaa −/− mice. Gait analyses showed reduced inter-limb inter-paw Electrophysiological single-unit proprioceptive afferents revealed sensitivity the dynamic static component stretch response. Finally, progressive degeneration sensory neuron intrafusal fibers was detectable observed increased abundance size lysosomes, fragmentation inner outer connective tissue capsule buildup autophagic vacuoles spindles from mice, indicating defects autophagocytosis. These results demonstrate structural altered Similar changes could patients disease.

Язык: Английский

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Massive reduction of RyR1 in muscle spindles of mice carrying recessiveRyr1mutations alters proprioception and causes scoliosis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 9, 2024

Abstract Muscle spindles are stretch receptors lying deep within the muscle belly involved in detecting changes length and playing a fundamental role motor control, posture synchronized gait. They made up of an external capsule surrounding 3-5 intrafusal fibers nuclear bag complex. Dysfunction leads to abnormal proprioceptor function, which has been linked aberrant bone cartilage development, scoliosis, kyphosis joint contractures. RYR1 , gene encoding calcium release channel sarcoplasmic reticulum, is most common target mutations human congenital myopathies, condition often accompanied by skeleton alterations So far, link between mutations, altered skeletal defects not investigated. To this end, we investigated heterozygous mice carrying recessive Ryr1 isogenic those present severely affected child. Here show that: (i) RyR1 protein localizes polar regions exhibits doubled row distribution pattern, typical for junctional reticulum proteins; (ii) compound structural defects; (iii) content from dHT reduced 54%. Such massive reduction mutant expression fiber proteins, severe alteration gait inter limb coordination. These results support hypothesis that only affect function extrafusal muscles, but might also muscles. The latter may be one underlying causes abnormalities seen patients mutations.

Язык: Английский

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Peripheral cranio-spinal nerve communication for trapezius muscle control using axonal profiling through immunostaining

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Окт. 25, 2024

Accessory nerve (CNXI) has been known to be the primary conduit for motor control of trapezius, while supplementary cervical nerves (C3 and C4) are responsible processing sensory information from muscle. However, lack substantial direct evidence led these conclusions being regarded as mere speculation. This study used immunostaining (using antibodies against neurofilament 200 all axons, choline acetyltransferase cholinergic tyrosine hydroxylase sympathetic alpha 3 sodium potassium ATPase proprioceptive afferent axons) human samples verify functional contributions nerves. Study highlights pivotal role C3 C4 in regulating precise movements contributing control, feedback, modulation. CNXI is composed primarily somatic efferent fibers, with significant numbers or fibers. Furthermore, C3-4 have both non-cholinergic suggesting their involvement feedback functions. Although less common, mechanosensors such nociceptive sensor fibers also supplied by The demonstrated that contain challenging long-held notion upper spinal sensory.

Язык: Английский

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Experimental Physiology special issue: ‘Mechanotransduction, muscle spindles and proprioception’

Experimental Physiology, Год журнала: 2023, Номер 109(1), С. 1 - 5

Опубликована: Дек. 31, 2023

This special issue of Experimental Physiology contains a collection 13 manuscripts based on oral presentations presented at the meeting 'Mechanotransduction, Muscle Spindles and Proprioception', which took place Ludwig-Maximilians-Universität in Munich July 2022. The participants included >30 speakers from Taiwan, Canada, Australia, USA, Israel all over Europe UK. In this Editorial, I want to present brief personal view how idea organize emerged put individual publications into perspective. Proprioception is essential for coordinated movements required perceiving position body space (Proske & Gandevia, 2012). Given that Aristotle (384–322 BC) first defined smell, sight, touch, taste hearing as five senses, proprioception has often been coined 'sixth' sense, despite >20 senses being known, with exact number remaining elusive. Although an integrative system processes information combination peripheral sensory input, including muscle length tension, joint angle skin stretch (Macefield Knellwolf, 2018), key components intricate are spindles (Matthews, 2015). Embedded almost every skeletal muscle, these primary proprioceptive organs relay constant about tone CNS (Kröger, 2018; Proske From information, spatial motion space, process crucial motor control, voluntary movement, posture stable gait Kröger Watkins, 2021). During its prime time 1950s 1960s, were forefront physiology, many basic principles discovered using spindles, including, example, rate coding stimulus intensity (Adrian Zotterman, 1926). For similar what neuromuscular junction had discovery principle synaptic transmission. fact, scientists working also worked Sir Charles Sherrington, Steven Kuffler Bernhard Katz (see e.g., Hunt Kuffler, 1951a, 1951b; Katz, 1950; 1907). tenuissimus cat become classic preparation, spindle function probably still best characterized particular (for more historical regarding muscles sense posture, see Molnar Brown, 2010). However, 1970s 1980s, interest declined, spindle/proprioception field mostly bypassed beginning 'molecular age'. changed past decade, leading identification new, surprising functions, have extended role far beyond sensing 2018). These rather recent discoveries include, Piezo2 channel main mechanotransduction (Woo et al., 2015), several diseases directly or indirectly affected (Kröger 2021), strong influence (Blecher proprioceptor subtypes (Dietrich 2022), maintaining locomotor robustness (i.e., ability cope perturbations; Santuz Akay, 2023) elucidation molecular basis differentiation signals during neuron development (Cheret 2013; Hippenmeyer 2002). Monoclonal antibodies confocal microscopy replaced silver impregnation techniques now widely applied characterize level. Single-cell single-nucleus sequencing intrafusal fibres neurons proteomics analysis provide platforms design specific markers cell populations (Blum 2021; Bornstein, Heinemann-Yerushalmi 2023; Dietrich 2022; Kim 2020; Oliver Unfortunately, who rediscovered revitalized last decade came different areas neuroscience did not know each other. Therefore, exchange ideas (equally important) passing young was difficult. There simply no where new findings their functional implications could be discussed. After visiting Guy Bewick Bob Banks Aberdeen Katherine Wilkinson San José, we agreed should held knowledge would merge latest concepts, overall scientific goal forum united international experts mechanotransduction, higher-order processing share knowledge, develop effective experimental strategies by initiating collaborations between researchers expertise. With focus mind, invited, everybody come Munich, further demonstrating need focus. itself started fantastic introduction perspective Banks. He summarized 50 years research structure mammalian spindle, innervation. addition, he quantitative morphological results equatorial nuclei endings relationship passive (Banks, 2024). session conversion mechanical change membrane potential). mechanosensitive loss-of-function mutations humans result muscular atrophy, perinatal respiratory distress, arthrogryposis scoliosis (Chesler 2016; Delle Vedove 2016). other channels must considered initial event, acid-sensing ion (ASIC) subtypes. Accordingly, covered ASICs function. substrate deformation-driven neurite micropipette-guided ultrasound knockout mouse models ASIC subtypes, Chih-Cheng Chen's laboratory analysed roles ASIC3 ASIC1a relying (Lin Using vivo proprioception-related behavioural assays ex electrophysiological analyses mice lacking ASIC2 shown display impairments responses coordination tasks, ASIC2s normal (Bornstein, Watkins Moreover, revealed deficits, impaired spinal alignment 2024), supporting important maintenance system. Collectively, studies identify mechanosensation. rapidly adapting, but response slowly there requirement additional elements maintain firing stretch. One such element glutamate. afferent contain glutamate-filled synaptic-like vesicles released stretch- calcium-dependent manner (Bewick, Consistently, blocking glutamate packaging vGluT1-containing transgenic one allele vesicular transporter vGluT1 decreases static dynamic sensitivity (Than led model calcium entering through can cause release vesicles, then helps depolarization firing. his presentation, gave evidence glutamate-sensitive contributing sustained initially identified metabotropic receptor coupled phospholipase D, homomeric GluK2 (Thompson Pharmacological, immunohistochemical biochemical expression terminals consistent hypothesis. pathological situations A rare autosomal recessive disease causing selective loss neurons, greatly elevated pain temperature thresholds, poor proprioception, marked ataxia disturbances blood pressure control hereditary autonomic neuropathy type III (HSAN III), known familial dysautonomia Riley–Day syndrome. Owing absence reflexes absent throughout body, leading, among things, compromised knee joint, acuity severe impairment. Surprisingly, elbow, patients perform poorly finger-to-nose test Purdue pegboard task, compared age-matched healthy subjects most likely explanation differential effect mutation that, contrast large-fibre (Cole Sedgwick, 1992) cutaneous afferents lost, HSAN access mechanoreceptors skin. future, like might allow accurate treatment symptoms after feedback provided spindles. Classical proprioceptors (muscle Golgi tendon organs) human facial (Cobo 2017; Omstead 2024) extraocular mammals. contrast, palisade some muscles, it suggested they structures, substitute functionally explain indicating brain eye position. Likewise, exhibit structural characteristics common classical proprioceptors. Interestingly, clear machinery calcium-mediated exocytosis acetylcholine (Blumer 2020). suggest complex, is, only features Two perception musculoskeletal pain. non-nociceptive, express ASICs, dual-function proteins proton mechanosensing. Thus, hypothesized associated tissue acidosis (Lee Chen, Consistent hypothesis, clinical deficit chronic fibromyalgia found training beneficial relief possibility microdamage caused, eccentric concentric exercise, respectively 2024; Lund 2010; Sas Large-diameter afferents, those innervating hyperexcitable spontaneous ectopic places away ending within capsule) conditions neuropathic Astrocytes, activated conditions, contribute generation firing, opening cross-talk nociceptive pathways occur periphery, capsule (Sas Clearly, limited direct nociception, acid signalling, damage astrocyte–sensory deserve investigation, because understanding approaches treatments Huub Maas addressed question whether activity attributable restricted homonymous adjacent joints/muscles (Maas Noort, study concluded changing affects behaviour neighbouring muscle. rotations 15° caused changes soleus condition joints does span part complex biological biophysical properties vital our vivo, age. fascicle biomechanics compliant older adults, decreased movement posture. Lena Ting's investigated effects increased compliance movement. Her attenuate rapid bursts onset decrease explained fully (Abbott Computational hypotheses predict behaviour. instance, if wants amputees physiologically relevant prosthesis. centred computational Researchers Tim Cope's developed time, integrates asymmetric distribution voltage-gated neuronal architecture generate realistic profiles determine parameters mechanosensory encoding (Housley, Powers model, showed subcellular ratios complementary and, instances, orthogonal means regulate stimuli. Another used ask cross-bridge dynamics shape encoded (Simha Ting, Results show both actin myosin interactions signals. incorporation necessary history-dependent line observations. tuned shows non-linear sinusoidal protocols emerge dynamics. summary, diverse aspects broad spectrum clearly contributed great success meeting, enthusiasm articulated comments reflected publish Physiology. talks truly excellent, discussions friendly point sometimes controversial Gardolinski established meeting. objectives bring together, discuss initiate synergies achieved. agenda therefore planned 2024. It remains thank involved helping me Most importantly, colleagues my Biomedical Center LMU (Bridgette Corinna Haupt, Zoi Gioga, Arlind Lamcaj Jürgen Schultheiss), without whose hard work, dedication co-ordination activities conference happened. acknowledge thankfully financial support German Research Foundation (DFG) industrial sponsors. Finally, Banks, together team Physiology, especially Diana Jones Alex Steward, unstinting patience compilation papers. Stephan wrote Editorial. accountable work questions related accuracy integrity any work. All persons designated authors qualify authorship, authorship listed. author declares competing interests relationships appeared reported paper. Group photo 1st Conference "Mechanotransduction, Proprioception" 2022 First row (from left right): S. Housley, L. T. Cope, G. Bewick, Kröger, D. Zytnicki Second row: Cole, A. Kolta, J. De Nooij, Brüggemann, C.-C. Chen Third Vedove, Agrawal, K. Wilkinson, B. H. Maas, Simha, Fourth C. Birchmeier, M. Meier, E. Zelzer, Picton, R. Blumer Fifth F. Zorzato, Treves (hidden), C.-H. Lee, Valdez, Passini, V. Macefield Last N. Zampieri, Griffith, Schoser.

Язык: Английский

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Macrophages reside in the muscle spindle to control sensorimotor function at millisecond timescale

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Окт. 11, 2023

Abstract The stretch reflex is a fundamental component of the motor system that orchestrates coordinated muscle contractions underlying movement. At heart this process lie spindles (MS), specialized receptors finely attuned to fluctuations in tension within intrafusal fibers. variation MS triggers series neuronal events; an initial depolarization sensory type Ia afferents subsequently causes activation motoneurons spinal cord. This cascade culminates execution contraction, underscoring presumed closed-loop mechanism between musculoskeletal and nervous systems. In contrast, surprisingly here we report discovery new population macrophages with exclusive molecular functional signatures spindle express machinery for synthesizing releasing glutamate. Using mouse intersectional genetics optogenetics electrophysiology, show (MSMP) drives proprioceptive neuron firing at millisecond timescale. activates circuits, neurons, muscles via glutamate-dependent mechanism. Additionally, found MSMP can also respond circuitry by increasing expression glutaminase, enabling them convert glutamine released myocytes during contraction into Our results have identified cellular component, MSMP, directly regulates neural activity contraction. glutamate-mediated signalling their dynamic response cues introduces novel dimension our understanding sensation action, potentially offering innovative therapeutic approaches conditions affect sensorimotor function.

Язык: Английский

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