Enhanced Voluntary Exercise Improves Functional Recovery following Spinal Cord Injury by Impacting the Local Neuroglial Injury Response and Supporting the Rewiring of Supraspinal Circuits

Loy, Kristina; Schmalz, Anja; Hoche, Tobias; Jacobi, Anne; Kreutzfeldt, Mario; Merkler, Doron; Bareyre, Florence M.

doi:10.1089/neu.2017.5544

Cited by 33 publications

(43 citation statements)

References 59 publications

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“…Recently, Gorgey et al showed that electrical stimulation-evoked resistance training (mimicking motor demands) combined with testosterone replacement therapy resulted in fiber hypertrophy and beneficial changes in markers of skeletal muscle health and function in persons with SCI 23 . The stimulation of fore/hindlimb muscles by rehabilitation exercise is used as a strategy to enhance stepping ability and respiratory recovery post SCI in both animal models and clinical studies 20,22,24 .These evidences reinforce the hypothesis that stimulation of limb muscles may be useful to improve respiratory rehabilitation post SCI. Nevertheless, little is known about the microvascular modulation and the effect of a non-invasive intervention (i.e.…”

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confidence: 58%

Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Jesus

Michel‐Flutot

Deramaudt

et al. 2021

Sci Rep

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Cervical spinal cord injury (SCI) results in permanent life-altering motor and respiratory deficits. Other than mechanical ventilation for respiratory insufficiency secondary to cervical SCI, effective treatments are lacking and the development of animal models to explore new therapeutic strategies are needed. The aim of this work was to demonstrate the feasibility of using a mouse model of partial cervical spinal hemisection at the second cervical metameric segment (C2) to investigate the impact of 6 weeks training on forced exercise wheel system on locomotor/respiratory plasticity muscles. To measure run capacity locomotor and respiratory functions, incremental exercise tests and diaphragmatic electromyography were done. In addition, muscle fiber type composition and capillary distribution were assessed at 51 days following chronic C2 injury in diaphragm, extensor digitorum communis (EDC), tibialis anterior (TA) and soleus (SOL) muscles. Six-week exercise training increased the running capacity of trained SCI mice. Fiber type composition in EDC, TA and SOL muscles was not modified by our protocol of exercise. The vascularization was increased in all muscle limbs in SCI trained group. No increase in diaphragmatic electromyography amplitude of the diaphragm muscle on the side of SCI was observed, while the contraction duration was significantly decreased in sedentary group compared to trained group. Cross-sectional area of type IIa myofiber in the contralateral diaphragm side of SCI was smaller in trained group. Fiber type distribution between contralateral and ipsilateral diaphragm in SCI sedentary group was affected, while no difference was observed in trained group. In addition, the vascularization of the diaphragm side contralateral to SCI was increased in trained group. All these results suggest an increase in fatigue resistance and a contribution to the running capacity in SCI trained group. Our exercise protocol could be a promising non-invasive strategy to sustain locomotor and respiratory muscle plasticity following SCI.

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confidence: 58%

Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Jesus

Michel‐Flutot

Deramaudt

et al. 2021

Sci Rep

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“…In fact, the combination of ChABC with rehabilitation led to less collateral crossing of BDA-loaded CST axons. Likewise, intense wheel-rehabilitation in mice following thoracic hemisection did not increase caudal serotonin immunofluorescence at 10 weeks post-SCI (Loy et al, 2018). This is complicated by the fact the contrary is also reported to occur (Engesser-Cesar et al, 2007;Maier et al, 2008).…”

Section: Discussionmentioning

confidence: 91%

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

Griffin

Fackelmeier

Clemett

et al. 2019

Preprint

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Chondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. Bacterial chondroitinase ABC degrades CSPGs and has been extensively reported to be therapeutic after SCI but there remain concerns for its clinical translation. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery after SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC 1 D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo, leading to widespread degradation of CSPGs. AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to the injury, and improved functional recovery after moderate contusive SCI.Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to enhanced functional recovery after SCI. Thus, widespread and long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a promising candidate for further preclinical development. AbbreviationsAAV Adeno-associated virus ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs ChABC Chondroitinase ABC CS-GAG Chondroitin sulphate glycosaminoglycan CSPG Chondroitin sulphate proteoglycan ECM Extracellular matrix GAG Glycosaminoglycan LV Lentiviral vector

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“…We observed a similar result after cortical stroke, Inpp5k overexpression enhanced sprouting of intact CSNs into the denervated side of the spinal cord without enhancing functional recovery. Without additional stimuli that can guide labile arbors to correct postsynaptic targets, such as rehabilitative training (Wahl et al, 2014; Serradj et al, 2017; Loy et al, 2018; Torres-Espin et al, 2018; Loy and Bareyre, 2019), it is not surprising that significant functional recovery is not observed after monogenic intervention.…”

Section: Discussionmentioning

confidence: 99%

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

Kauer

Fink

et al. 2021

Preprint

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Failure of CNS neurons to mount a significant intrinsic growth response after trauma results in chronic functional deficits after spinal cord injury. Approaches to identify novel axon growth activators include transcriptional and repressor screening of embryonic cortical and retinal ganglion neurons in vitro. These high throughput approaches have identified several candidates; however, their inability to comprehensively model the adult CNS has resulted in their exploitation in vivo failing to stimulate significant anatomical and functional gains. To identify novel cell autonomous axon growth activators while maintaining CNS complexity, we screened intact adult corticospinal neurons (CSNs) undergoing functional plasticity after unilateral pyramidotomy. RNA-seq of intact sprouting corticospinal tract (CST) axons showed an enrichment of genes in the 3-phosphoinositide degradation pathways, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K (Inpp5k) could enhance CST axon growth in clinical models of CNS trauma. Overexpression of Inpp5k in intact adult CSNs enhanced sprouting of intact CST terminals into the denervated cervical cord after pyramidotomy and cortical stroke lesion. Inpp5k overexpression also stimulated sprouting of CST axons in the cervical cord after acute and chronic severe thoracic spinal contusion. We show that Inpp5k stimulates axon growth by elevating the density of active cofilin in the cytosol of labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. This study identifies Inpp5k as a novel CST growth activator and underscores the veracity of using in vivo transcriptional screening to identify the next generation of cell autonomous factors capable of repairing the damaged CNS.

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Enhanced Voluntary Exercise Improves Functional Recovery following Spinal Cord Injury by Impacting the Local Neuroglial Injury Response and Supporting the Rewiring of Supraspinal Circuits

Cited by 33 publications

References 59 publications

Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Effects of aerobic exercise training on muscle plasticity in a mouse model of cervical spinal cord injury

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma

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