Mechanism of skeletal muscle atrophy after spinal cord injury: A narrative review

Zhu Z., Wang X., Song Z., Zuo X., Ma Y., Zhang Z., Ju C., Liang Z., Li K., Hu X., Wang Z.

Background: Insufficient neuronal mitochondrial bioenergetics supply occurs after spinal cord injury (SCI), leading to neuronal apoptosis and impaired motor function. Previous reports have shown that photobiomodulation (PBM) could reduce neuronal apoptosis and promote functional recovery, but the underlying mechanism remains unclear. Therefore, we aimed to investigate whether PBM improved prognosis by promoting neuronal mitochondrial bioenergetics after SCI.Methods: Sprague Dawley rats were randomly divided into four groups: a Sham group, an SCI group, an SCI + PBM group and an SCI + PBM + Compound C group. After SCI model was established, PBM and Compound C (an AMPK inhibitor) injection were carried out. The level of neuron apoptosis, the recovery of motor function and mitochondrial function were observed at different times (7, 14, and 28 days). The AMPK/PGC-1α/TFAM pathway was hypothesized to be a potential target through which PBM could affect neuronal mitochondrial bioenergetics. In vitro, ventral spinal cord 4.1 (VSC4.1) cells were irradiated with PBM and cotreated with Compound C after oxygen and glucose deprivation (OGD).Results: PBM promoted the recovery of mitochondrial respiratory chain complex activity, increased ATP production, alleviated neuronal apoptosis and reversed motor dysfunction after SCI. The activation of the AMPK/PGC-1α/TFAM pathway after SCI were facilitated by PBM but inhibited by Compound C. Equally important, PBM could inhibit OGD-induced VSC4.1 cell apoptosis by increasing ATP production whereas these changes could be abolished by Compound C.Conclusion: PBM activated AMPK/PGC-1α/TFAM pathway to restore mitochondrial bioenergetics and exerted neuroprotective effects after SCI.

Stratos I., Behrendt A., Anselm C., Gonzalez A., Mittlmeier T., Vollmar B.

Background: Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury. Materials and methods: Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment. Results: Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups. Conclusions: These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury.

Meijboom K.E., Sutton E.R., McCallion E., McFall E., Anthony D., Edwards B., Kubinski S., Tapken I., Bünermann I., Hazell G., Ahlskog N., Claus P., Davies K.E., Kothary R., Wood M.J., et. al.

Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn−/−; SMN2 and the less severe Smn2B/− SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak−/−, and Fn14−/− mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Rosales-Antequera C., Viscor G., Araneda O.F.

One of the etiopathogenic factors frequently associated with generalized organ damage after spinal cord injury corresponds to the imbalance of the redox state and inflammation, particularly of the respiratory, autonomic and musculoskeletal systems. Our goal in this review was to gain a better understanding of this phenomenon by reviewing both animal and human studies. At the respiratory level, the presence of tissue damage is notable in situations that require increased ventilation due to lower thoracic distensibility and alveolar inflammation caused by higher levels of leptin as a result of increased fatty tissue. Increased airway reactivity, due to loss of sympathetic innervation, and levels of nitric oxide in exhaled air that are similar to those seen in asthmatic patients have also been reported. In addition, the loss of autonomic control efficiency leads to an uncontrolled release of catecholamines and glucocorticoids that induce immunosuppression, as well as a predisposition to autoimmune reactions. Simultaneously, blood pressure regulation is altered with vascular damage and atherogenesis associated with oxidative damage. At the muscular level, chronically elevated levels of prooxidants and lipoperoxidation associated with myofibrillar atrophy are described, with no reduction or reversibility of this process through antioxidant supplementation.

Jervis Rademeyer H., Gauthier C., Zariffa J., Walden K., Jeji T., McCullum S., Musselman K.E.

To understand if and how physical therapists (PTs) and occupational therapists (OTs) use activity-based therapy (ABT) and its associated technologies for the rehabilitation of individuals living with spinal cord injury or disease (SCI/D) in Canadian rehabilitation hospital settings.Qualitative study.Through rehabilitation hospitals participating in the Rick Hansen Spinal Cord Injury Registry, we recruited licensed OTs and PTs to participate in focus groups.Twelve PTs and ten OTs from nine sites across eight provinces participated.To inform the development of a semi-structured interview guide, we used the Theoretical Domains Framework. To analyze the data, we used interpretive description.We identified three themes that influenced therapists' use of ABT and associated technologies for SCI/D rehabilitation. (1) Therapists' decision-making approach to ABT and technology. Therapist roles, site-specific dynamics and goal setting influenced decision-making. Assuming roles such as mentor, liaison and advocate led to more ABT use. Site-specific dynamics concerned levels of ABT knowledge, teamwork, and staffing. In hospital rehabilitation, there was competition between discharge and neurorecovery goals. (2) Therapist perceived individual factors. Patient factors either increased (i.e. patients' motivation, self-advocacy) or prevented (i.e. mourning period, tolerance) the likelihood that ABT was introduced by therapists. (3) ABT and equipment access. Technology was used for ABT in a variety of ways. Access was affected by visible (e.g. equipment cost) and invisible barriers (e.g. departmental relations).The use of ABT and its associated technologies in Canadian rehabilitation hospitals is variable. Ongoing education could be offered, and site-specific implementation strategies could be developed, to promote ABT use.

Grgic J., Schoenfeld B.J., Orazem J., Sabol F.

We aimed to perform a systematic review and meta-analysis of the effects of training to muscle failure or non-failure on muscular strength and hypertrophy.Meta-analyses of effect sizes (ESs) explored the effects of training to failure vs. non-failure on strength and hypertrophy. Subgroup meta-analyses explored potential moderating effects of variables such as training status (trained vs. untrained), training volume (volume equated vs. volume non-equated), body region (upper vs. lower), exercise selection (multi- vs. single-joint exercises (only for strength)), and study design (independent vs. dependent groups).Fifteen studies were included in the review. All studies included young adults as participants. Meta-analysis indicated no significant difference between the training conditions for muscular strength (ES = -0.09, 95% confidence interval (95%CI): -0.22 to 0.05) and for hypertrophy (ES = 0.22, 95%CI: -0.11 to 0.55). Subgroup analyses that stratified the studies according to body region, exercise selection, or study design showed no significant differences between training conditions. In studies that did not equate training volume between the groups, the analysis showed significant favoring of non-failure training on strength gains (ES = -0.32, 95%CI: -0.57 to -0.07). In the subgroup analysis for resistance-trained individuals, the analysis showed a significant effect of training to failure for muscle hypertrophy (ES = 0.15, 95%CI: 0.03-0.26).Training to muscle failure does not seem to be required for gains in strength and muscle size. However, training in this manner does not seem to have detrimental effects on these adaptations, either. More studies should be conducted among older adults and highly trained individuals to improve the generalizability of these findings.

López-Seoane J., Jiménez S.L., Del Coso J., Pareja-Galeano H.

The use of omega-3 polyunsaturated fatty acids (n-3 PUFA) has been studied in physically active population, however, there is a lack of information about the effects of n-3 PUFA supplementation on people with a sedentary behavior or who are undergoing a period of limb immobilization. This systematic review aims to examine the effect of n-3 PUFA on lean mass and muscle protein synthesis (MPS) in absence of physical training. The PubMed, Web of Science, MEDLINE, CINAHL and SPORTDiscus databases were searched following the PRISMA guidelines. Only randomized controlled trials, at least single blind, performed with sedentary humans were considered. Seven studies on a total of 192 individuals were included. Five of the six studies which measured changes in skeletal muscle volume and mass showed higher values with n-3 PUFA. Only two studies measured skeletal muscle protein expression. Both showed beneficial effects of supplementation in muscle protein fractional synthesis rate (FSR), while no effect of n-3 PUFA was observed for mechanistic target of rapamycin (mTOR) and kinase protein (Akt). In addition, ribosomal protein S6 kinase 1 (p70s6k) improved with n-3 PUFA only in one study. Finally, the two studies which measured the skeletal muscle gene expression observed no effect of supplementation.

Feng L., Li B., Xi Y., Cai M., Tian Z.

Myocardial infarction (MI)-induced heart failure (HF) is commonly accompanied with profound effects on skeletal muscle. With the process of MI-induced HF, perturbations in skeletal muscle contribute to muscle atrophy. Exercise is viewed as a feasible strategy to prevent muscle atrophy. The aims of this study were to investigate whether exercise could alleviate MI-induced skeletal muscle atrophy via insulin-like growth factor 1 (IGF-1) pathway in mice. Male C57/BL6 mice were used to establish the MI model and were divided into three groups: sedentary MI group (MI), MI with aerobic exercise group, and MI with resistance exercise group; sham-operated group was used as control. Exercise-trained animals were subjected to 4 wk of aerobic exercise (AE) or resistance exercise (RE). Cardiac function, muscle weight, myofiber size, levels of IGF-1 signaling and proteins related to myogenesis, protein synthesis, and degradation and apoptosis in gastrocnemius muscle were detected. H2O2-treated C2C12 cells were intervened with recombinant human IGF-1, IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, and PI3K inhibitor LY294002 to explore the mechanism. Exercises upregulated the IGF-1/IGF-1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling; increased the expressions of Pax7, myogenic regulatory factors (MRFs), and protein synthesis; and reduced protein degradation and cell apoptosis in MI mice. In vitro, IGF-1 upregulated the levels of Pax7, MRFs, mTOR, and P70S6K; reduced MuRF1 and MAFbx; and inhibited cell apoptosis via IGF-1R-PI3K/Akt pathway. AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation, and cell apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt signaling pathway.

Sutor T.W., Kura J., Mattingly A.J., Otzel D.M., Yarrow J.F.

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.

Chen Y., Huang T., Yu Z., Yu Q., Wang Y., Hu J., Shi J., Yang G.

Sestrins (Sesns), highly conserved stress-inducible metabolic proteins, are known to protect organisms against various noxious stimuli including DNA damage, oxidative stress, starvation, endoplasmic reticulum (ER) stress, and hypoxia. Sesns regulate metabolism mainly through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Sesns also play pivotal roles in autophagy activation and apoptosis inhibition in normal cells, while conversely promoting apoptosis in cancer cells. The functions of Sesns in diseases such as metabolic disorders, neurodegenerative diseases, cardiovascular diseases, and cancer have been broadly investigated in the past decades. However, there is a limited number of reviews that have summarized the functions of Sesns in the pathophysiological processes of human diseases, especially musculoskeletal system diseases. One aim of this review is to discuss the biological functions of Sesns in the pathophysiological process and phenotype of diseases. More significantly, we include some new evidence about the musculoskeletal system. Another purpose is to explore whether Sesns could be potential biomarkers or targets in the future diagnostic and therapeutic process.

Ding Y., Chen Q.

Spinal cord injury (SCI) is the most common disabling spinal injury, and the complex pathological process can eventually lead to severe neurological dysfunction. Many studies have reported that the mammalian target of rapamycin (mTOR) signaling pathway plays an important role in synaptogenesis, neuron growth, differentiation, and survival after central nervous system injury. It is also involved in various traumatic and central nervous system diseases, including traumatic brain injury, neonatal hypoxic-ischemic brain injury, Alzheimer's disease, Parkinson's disease, and cerebral apoplexy. mTOR has also been reported to play an important regulatory role in various pathophysiological processes following SCI. Activation of mTOR signals after SCI can regulate physiological and pathological processes, such as proliferation and differentiation of neural stem cells, regeneration of nerve axons, neuroinflammation, and glial scar formation, through various pathways. Inhibition of mTOR activity has been confirmed to promote repair in SCI. At present, many studies have reported that Chinese herbal medicine can inhibit the SCI-activated mTOR pathway to improve the microenvironment and promote nerve repair after SCI. Due to the role of the mTOR pathway in SCI, it may be a potential therapeutic target for SCI. This review is focused on the pathophysiological process of SCI, characteristics of the mTOR pathway, role of the mTOR pathway in SCI, role of inhibition of mTOR on SCI, and role and significance of inhibition of mTOR by related Chinese herbal medicine inhibitors in SCI. In addition, the review discusses the deficiencies and solutions to mTOR and SCI research shortcomings. This study hopes to provide reference for mTOR and SCI research and a theoretical basis for SCI biotherapy.

Hertig-Godeschalk A., Brinkhof M.W., Scheel-Sailer A., Perret C., Jenny A., Landmann G., Wyss P.O., Flueck J.L.

IntroductionVitamin D insufficiency, a vitamin D status or serum 25(OH)D concentration of ≤75 nmol/L, is highly prevalent in individuals with a spinal cord injury (SCI). Vitamin D is important for the functioning of the musculoskeletal, immune and respiratory systems, which are relevant determinants of secondary health conditions in SCI. An insufficiency should be treated with vitamin D supplementation. However, there is a lack of evidence regarding the optimal dosage and duration of vitamin D supplementation for individualised and long-term management of the vitamin D status in the context of SCI. This paper presents the protocol for the vitamin D supplementation in chronic spinal cord injury (VitD-SCI) trial that aims to investigate the effect of a 12-month intake of vitamin D supplementation on vitamin D status as well as on several secondary parameters among individuals with a chronic SCI.Methods and analysesThe VitD-SCI trial is a randomised, placebo-controlled, double-blinded, parallel-group, superiority trial, conducted at the Swiss Paraplegic Centre. A total of 45 participants living with an SCI for at least 3 years (chronic SCI) and a vitamin D insufficiency at the first study visit, will be randomly assigned to one of three intervention groups. Participants receive either a monthly dosage of 24 000 IU or 48 000 IU vitamin D or a placebo for 12 months. Measurements taking place every 3 months include the assessment of vitamin D status (primary outcome) as well as bone mineral density, handgrip strength, fatigue, mood, pain and pressure injuries (secondary outcomes). Safety and tolerance of vitamin D supplementation will also be evaluated.Ethics and disseminationThe Swiss Ethics Committee for Northwest/Central Switzerland (EKNZ, 2020–01493) and the Swiss Agency for Therapeutic Products (Swissmedic, 2020DR3150) approved this study. Findings will be disseminated through peer-reviewed publications.Trial registration numbersNCT04652544 and SNCTP000004032.

Tseng H., Kulina I., Girard D., Gueguen J., Vaquette C., Salga M., Fleming W., Jose B., Millard S.M., Pettit A.R., Schroder K., Thomas G., Wheeler L., Genêt F., Banzet S., et. al.

Neurogenic heterotopic ossifications (NHOs) form in periarticular muscles after severe spinal cord (SCI) and traumatic brain injuries. The pathogenesis of NHO is poorly understood with no effective preventive treatment. The only curative treatment remains surgical resection of pathological NHOs. In a mouse model of SCI-induced NHO that involves a transection of the spinal cord combined with a muscle injury, a differential gene expression analysis revealed that genes involved in inflammation such as interleukin-1β (IL-1β) were overexpressed in muscles developing NHO. Using mice knocked-out for the gene encoding IL-1 receptor (IL1R1) and neutralizing antibodies for IL-1α and IL-1β, we show that IL-1 signaling contributes to NHO development after SCI in mice. Interestingly, other proteins involved in inflammation that were also overexpressed in muscles developing NHO, such as colony-stimulating factor-1, tumor necrosis factor, or C-C chemokine ligand-2, did not promote NHO development. Finally, using NHO biopsies from SCI and TBI patients, we show that IL-1β is expressed by CD68+ macrophages. IL-1α and IL-1β produced by activated human monocytes promote calcium mineralization and RUNX2 expression in fibro-adipogenic progenitors isolated from muscles surrounding NHOs. Altogether, these data suggest that interleukin-1 promotes NHO development in both humans and mice. © 2021 American Society for Bone and Mineral Research (ASBMR).

Raiteri T., Zaggia I., Reano S., Scircoli A., Salvadori L., Prodam F., Filigheddu N.

Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.

Yan B., Zeng C., Chen Y., Huang M., Yao N., Zhang J., Yan B., Tang J., Wang L., Zhang Z.

Mechanical stress promotes human ligamentum flavum cells (LFCs) to synthesize multitype collagens, leading to ligamentum flavum hypertrophy (LFH). However, the mechanism of mechanical stress in the formation of collagen remains unclear. Therefore, we investigated the relationship between mechanical stress and collagen synthesis in the present study. First, LFCs were isolated from 9 patients and cultured with or without mechanical stress exposure for different times. IGF-1, collagen I (col-I), and collagen III (col-III) protein and mRNA levels were then detected via ELISA and qPCR, respectively. Moreover, the activation of pIGF-1R, pAKT, and pS6 was examined by Western blot analysis. To further explore the underlying mechanism, an IGF-1 neutralizing antibody, NVP-AEW541, and rapamycin were used. IGF-1, col-I, and col-III were significantly increased in stressed LFCs compared to nonstressed LFCs. In addition, the activation of pIGF-1R, pAKT, and pS6 was obviously enhanced in stressed LFCs. Interestingly, col-I protein, col-I mRNA, col-III protein, col-III mRNA, and IGF-1 protein, but not IGF-1 mRNA, were inhibited by IGF-1 neutralizing antibody. In addition, col-I and col-III protein and mRNA, but not IGF-1, were inhibited by both NVP-AEW541 and rapamycin. Moreover, the activation of pIGF-1R, pAKT, and pS6 was reduced by the IGF-1 neutralizing antibody and NVP-AEW541, and the activation of pS6 was reduced by rapamycin. In summary, these results suggested that mechanical stress promotes LFCs to produce IGF-1, which facilitates col-I and col-III synthesis via the IGF-1R/AKT/mTORC1 signaling pathway.

Sysoev Y.I., Shkorbatova P.Y., Prikhodko V.A., Kalinina D.S., Bazhenova E.Y., Okovityi S.V., Bader M., Alenina N., Gainetdinov R.R., Musienko P.E.

Spinal cord injury (SCI) affects millions of people worldwide. One of the main challenges of rehabilitation strategies is re-training and enhancing the plasticity of the spinal circuitry that was preserved or rebuilt after the injury. The serotonergic system appears to be crucial in these processes, since recent studies have reported the capability of serotonergic (5-HT) axons for axonal sprouting and regeneration in response to central nervous system (CNS) trauma or neurodegeneration. We took advantage of tryptophan hydroxylase 2 knockout (TPH2 KO) rats, lacking serotonin specifically in the brain and spinal cord, to study the role of the serotonergic system in the recovery of sensorimotor function after SCI. In the present work, we compared the rate of sensorimotor recovery of TPH2 KO and wild-type (WT) female rats after SCI (lateral hemisection at the T8 spinal level). SCI caused severe motor impairments in the ipsilateral left hindlimb, the most pronounced in the first week after the hemisection with gradual functional recovery during the following 3 weeks. The results demonstrate that TPH2 KO rats have less potential to recover motor functions since the degree of sensorimotor deficit in the tapered beam walking test (TBW) and ladder walking test (LW) was significantly higher in the TPH2 KO group in comparison to the WT animals in the 3rd and 4th weeks after SCI. The recovery dynamics of the hindlimb muscle tone and voluntary movements was in agreement with the restoration of motor performance in TBW and LW. Compound muscle action potential analysis in the gastrocnemius (GM) and tibialis (TA) muscles of both hindlimbs after electrical stimulation of the sciatic nerve or lumbar region (L5–L6) of the spinal cord indicated slower recovery of sensorimotor pathways in the TPH2 KO group versus their WT counterparts. In general, the observed results confirm the significance of central serotonergic mechanisms in the recovery of sensorimotor functions in rats and the relevance of the TPH2 KO rat model in studying the role of the 5-HT system in neurorehabilitation.

Sanna N., Nossa R., Biffi E., Guanziroli E., Diella E., Ferrante S., Molteni F., Peruzzo D., Casali N., Mastropietro A., Rizzo G., Tarabini M., Pedrocchi A., Ambrosini E.

Martínez-Torija M., Esteban P.F., Santos-de-la-Mata A., Castillo-Hermoso M., Molina-Holgado E., Moreno-Luna R.

Background/Objectives: Spinal cord injury (SCI) is a complex medical condition with widespread effects that extend beyond motor and sensory impairments. In addition to nervous system damage, SCI patients experience various secondary complications, including vascular dysfunction, altered body composition, and metabolic disturbances. Among the most common secondary pathologies is the development of pressure injuries (PIs), chronic wounds that significantly affect quality of life and can be challenging to treat. Understanding the physiological and cellular mechanisms behind these complications is crucial for improving care and therapeutic outcomes. Methods: We conducted a comprehensive literature search in PubMed, Scopus, and Google Scholar using keywords related to spinal cord injury, pressure ulcer/pressure injuries, metabolic and vascular dysfunction, biomechanics, and regenerative therapies. Studies were selected based on their relevance to the pathophysiology, risk factors, and novel therapeutic approaches for PIs in SCI patients. Results: Vascular dysfunction, characterized by impaired blood flow and microcirculatory issues, predisposes SCI patients to ischemia and tissue necrosis, particularly in areas subjected to prolonged pressure. Additionally, changes in body composition, such as increased adiposity and muscle atrophy, further compromise tissue integrity and healing capacity. The inflammatory response, mediated by cytokines such as IL-1, IL-6, and TNF-α, exacerbates these effects by sustaining a pro-inflammatory environment that delays the transition of macrophages to the M2 phenotype, critical for wound healing. External factors, such as poor nutrition, infections, and immobility, also play a significant role in worsening the wound healing process. Conclusions: Chronic SCI induces a cascade of physiological changes that predispose patients to the development of PIs and complicate their recovery. The intricate interplay of vascular, metabolic, and inflammatory responses creates a hostile environment for wound healing. A deeper understanding of these systemic effects is essential not only for developing targeted therapeutic strategies to improve chronic wound healing but also for refining preventive approaches that minimize their occurrence. Advancing this knowledge will ultimately help enhance the quality of life for individuals with SCI.

Hill B., Mitchell A., Szydlowska A., Sparks C., Dunn H., Berry H.

Nutrition plays a vital role in wound healing, influencing both the speed and quality of recovery. The wound healing process encompasses haemostasis, inflammation, proliferation, and remodelling, each reliant on specific nutrients. This article summarises the current literature on the role of nutrition in wound healing, focusing on key nutrients: proteins, vitamins (A, C, E, K), and minerals (zinc, iron, copper, manganese), essential for collagen synthesis, immune function, and cellular activity. Nurses are pivotal in assessing nutritional status, implementing dietary interventions, and educating patients and caregivers about the importance of nutrition in wound care. Practical strategies include personalised dietary plans, appropriate use of nutritional supplements, and regular monitoring of nutritional intake and wound healing progress. Although the benefits of nutrition in wound healing are well established, challenges persist, particularly in the limited evidence beyond pressure injuries and the constrained efficacy of supplementation without deficiencies. A multidisciplinary approach is critical to optimise nutritional support and improve patient outcomes in wound healing.

Tobener V W., Lynn R.S., Castillo C.

Bu Z., Jing J., Liu W., Fan Z., Huang J., Zhou Z., Hu J., An J., Hong J., Yu J., Tang D., Sun M., Du J., Wu P.

AbstractDenervated muscle atrophy, a common outcome of nerve injury, often results in irreversible fibrosis due to the limited effectiveness of current therapeutic interventions. While extracellular vesicles (EVs) offer promise for treating muscle atrophy, their therapeutic potential is hindered by challenges in delivery and bioactivity within the complex microenvironment of the injury site. To address this issue, an injectable hydrogel is developed that is responsive to both ultrasound and pH, with inherent anti‐inflammatory and antioxidant properties, designed to improve the targeted delivery of stem cell‐derived EVs. This hydrogel system allows for controlled release of EVs from human umbilical cord mesenchymal stem cells (HUC‐MSCs), adapting to the specific conditions of the injury environment. In vivo studies using a rat model of nerve injury demonstrated that the EV‐loaded hydrogel (EVs@UR‐gel) significantly preserved muscle function. Six weeks post‐nerve reconstruction, treated rats exhibited muscle strength, circumference, and wet weight reaching 89.53 ± 0.96%, 76.02 ± 7.49%, and 88.0 ± 2.65% of healthy controls, respectively, alongside an improvement in the sciatic nerve index (−0.11 ± 0.09). This platform presents a novel therapeutic approach by maintaining EV bioactivity, enabling tunable release based on the disease state, and facilitating the restoration of muscle structure and function.

Jiang Z., Wang K., Zhang H., Weng Y., Guo D., Ma C., Lu W.W., Xu H., Liu X.

This study aimed to elucidate the correlation between the degree of fat infiltration (FI) in thoracic paraspinal muscles and thoracic vertebral degeneration (TVD). This cross-sectional study comprised 474 patients who underwent standard thoracic computed tomography (CT) scans. The FI was quantified as the percentage of adipose tissues within the cross-sectional area of thoracic paraspinal muscles. Thoracic vertebra was assessed in terms of osteoporosis, ossification of the anterior longitudinal ligament (OALL), ossification of the posterior longitudinal ligament (OPLL), intervertebral disc calcification, intervertebral disc cavity, and facet joint osteoarthritis (FJO). Logistic regression, linear regression, subgroup, and receiver operating characteristic (ROC) analyses were assessed to evaluate the association between FI and TVD. Multivariate logistic regression revealed that more severe FI was closely associated with more serious osteoporosis (P < 0.001). Furthermore, after adjusting for only age, higher FI was significantly associated with nastier FJO (P < 0.05). In male patients, severe FI was greatly associated with worse osteoporosis (P < 0.05). In female patients, severe FI maintained close correlations with more severe osteoporosis and FJO (P < 0.05). Furthermore, in patients aged < 60 or ≥ 60 years, higher FI had a strong correlation with more severe osteoporosis (P < 0.001). In patients aged < 60 years, higher FI was associated with worse intervertebral disc calcification, OALL, and FJO (P < 0.05). Meanwhile, in patients aged ≥ 60 years, increased FI was only associated with severe OPLL (P < 0.05). Multivariate linear regression showed that FI negatively correlated with bone mineral density in the general population and different sex and age groups (P < 0.001). ROC analysis indicated that FI could predict the occurrence of TVD (P < 0.05). Higher FI is associated with more severe TVD. Studies on TVD are currently limited; therefore, this study enriches the related research on TVD, and our findings would facilitate the early prediction and diagnosis of TVD in clinical practice. Furthermore, our findings indicate that thoracic spine pain (TSP) caused by TVD can be prevented, potentially improving the prognosis of patients with TSP.

Jønsson A.B., Krogh S., Lillelund S., Aagaard P., Kasch H., Nielsen J.F.

ABSTRACTThe objective of the present study was to evaluate the efficacy of low‐load (LL) blood flow restriction exercise (BFRE) for improving lower limb muscle strength, muscle thickness and physical function in individuals with spinal cord injury (SCI). In a randomized sham‐controlled trial, 21 participants (age ≥ 18 years, SCI duration ≥ 1 year, knee extensor strength grade 2–4, ASIA A‐D) were randomized to either 45‐min LL‐BFRE (n = 11) or sham BFRE (n = 10) twice/week for 8 weeks. The exercise protocol consisted of four sets (30 × 15 × 15 × 15 repetitions) of unilateral seated leg extensions and leg curls at 30%–40% of 1RM performed with pneumatic cuffs applied proximally on the trained limb and inflated to 40% of total arterial occlusion pressure (BFRE) or non‐inflated (sham exercise). Maximal voluntary isometric quadriceps and hamstring muscle strength, quadriceps muscle thickness, thigh circumference, and physical function were assessed at baseline, after 4 and 8 weeks of training and at 4‐week follow‐up. No significant between‐group differences were found between BFRE and sham exercise in quadriceps or hamstring muscle strength, 10‐m walking test, timed up & go, 6‐min walking test or the spinal cord independence measure. In contrast, a significant between‐group difference favoring BFRE was present for muscle thickness and thigh circumference from baseline to 4‐week follow‐up (0.76 cm (95% CI: 0.32; 1.20, p = 0.002) and 2.42 cm (0.05; 4.79, p = 0.05), respectively). In conclusion, there was no significant difference in the effect of LL‐BFRE and sham exercise on muscle strength and physical function in individuals with SCI. However, significant increases in muscle thickness and thigh circumference were observed in favor of BFRE.Trial Registration: ClinicalTrials.gov identifier: NCT03690700.

Tretter B.L., Dolbow D.R., Ooi V., Farkas G.J., Miller J.M., Deitrich J.N., Gorgey A.S.

Emanating from several decades of study into the effects of the aging process after spinal cord injury (SCI), “accelerated aging” has become a common expression as the SCI accelerates the onset of age-related pathologies. However, the aging process follows a distinct trajectory, characterized by unique patterns of decline that differ from those observed in the general population without SCI. Aging brings significant changes to muscles, bones, and hormones, impacting overall physical function. Muscle mass and strength begin to decrease with a reduction in muscle fibers and impaired repair mechanisms. Bones become susceptible to fractures as bone density decreases. Hormonal changes combined with decreased physical activity accelerate the reduction of muscle mass and increase in body fat. Muscle atrophy and skeletal muscle fiber type transformation occur rapidly and in a unique pattern after SCI. Bone loss develops more rapidly and results in an increased risk of fractures in body regions unique to individuals with SCI. Other factors, such as excessive adiposity, decreased testosterone and human growth hormone, and increased systemic inflammation, contribute to a higher risk of neuropathically driven obesity, dyslipidemia, glucose intolerance, insulin resistance, and increasing cardiovascular disease risk. Cardiorespiratory changes after SCI result in lower exercise heart rates, decreased oxygenation, and mitochondrial dysfunction. While it is important to acknowledge the accelerated aging processes after SCI, it is essential to recognize the distinct differences in the aging process between individuals without physical disabilities and those with SCI. These differences, influenced by neuropathology, indicate that it may be more accurate to describe the aging process in individuals with chronic SCI as neurogenic accelerated aging (NAA). Research should continue to address conditions associated with NAA and how to ameliorate the accelerated rate of premature age-related conditions. This review focuses on the NAA processes and the differences between them and the aging process in those without SCI. Recommendations are provided to help slow the development of premature aging conditions.

Kim S., Han K., Kim B., Min J., Chang W.H., Cho I.Y., Shin D.W.

Objectives: Estimating the risk of diabetes mellitus (DM) is important for the proper management of patients with spinal cord injury (SCI). We investigated the short-term and long-term risks of DM among patients with SCI, according to the presence or severity of post-SCI disability and the level of injury. Methods: We conducted a retrospective cohort study using the Korean National Health Insurance Service (2010–2018) database. After matching by age and sex, 6129 SCI patients and 22,979 controls were included. The primary outcome was incident DM, and risk was evaluated for both the short term (within 1 year after SCI) and the long term (after 1 year of SCI diagnosis). Results: The risk of DM was higher among patients with cervical- and thoracic-level SCI accompanied by disability compared to the controls during follow-up (4.6 ± 2.6 years). The short-term risk of DM was higher among patients with SCI (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.91–3.27) than among the controls and it was even higher among patients with severe disability (OR 5.38, 95% CI 2.91–9.27). According to the level of injury, patients with cervical SCI had the highest short-term risk of DM (with disability, OR 4.93, 95% CI 3.07–7.63). There was no significant increase of DM risk in the long term, after 1 year of SCI diagnosis. Conclusions: Patients with SCI accompanied by severe disability and cervical-level injury had higher risks of pronounced DM in the short term. The findings of this study emphasize the need for active surveillance of DM among patients with high-level SCI and disability, especially in the short term, in addition to continuous monitoring and proper management of DM in the long term.

Nemeth C., Banik N.L., Haque A.

The neuromuscular junction (NMJ) is a crucial structure that connects the cholinergic motor neurons to the muscle fibers and allows for muscle contraction and movement. Despite the interruption of the supraspinal pathways that occurs in spinal cord injury (SCI), the NMJ, innervated by motor neurons below the injury site, has been found to remain intact. This highlights the importance of studying the NMJ in rodent models of various nervous system disorders, such as amyotrophic lateral sclerosis (ALS), Charcot–Marie–Tooth disease (CMT), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). The NMJ is also involved in myasthenic disorders, such as myasthenia gravis (MG), and is vulnerable to neurotoxin damage. Thus, it is important to analyze the integrity of the NMJ in rodent models during the early stages of the disease, as this may allow for a better understanding of the condition and potential treatment options. The spinal cord also plays a crucial role in the functioning of the NMJ, as the junction relays information from the spinal cord to the muscle fibers, and the integrity of the NMJ could be disrupted by SCI. Therefore, it is vital to study SCI and muscle function when studying NMJ disorders. This review discusses the formation and function of the NMJ after SCI and potential interventions that may reverse or improve NMJ dysfunction, such as exercise, nutrition, and trophic factors.

Gherle A., Nistor-Cseppento C.D., Iovanovici D., Cevei I.R., Cevei M.L., Vasileva D., Deac S., Stoicanescu D.

Background: Sarcopenia and spinal cord injury (SCI) often coexist, but little is known about the associations. This study aimed to assess the impact of SCI on muscle and bone mass and the correlations between the clinical characteristics of SCI patients and sarcopenia. Methods: A total of 136 patients with SCI admitted to rehabilitation hospital were included in this study. The type and severity of injury (AIS), level of spasticity (MAS), bone mineral density and Appendicular Lean Muscle Mass (ALM) were assessed. Sarcopenia was diagnosed according to EWGSOP2 cut-off points for ALM. Results: Subjects were divided into two groups: Group S-SCI (N = 66, sarcopenia group) and Group NS-SCI (N = 70, without sarcopenia). Mean ALM values in the two groups were 0.49 and 0.65, respectively. A total of 75% of women and 42.9% of men developed sarcopenia. The mean age was 35.8 years in the sarcopenic patients and 41.5 in the non-sarcopenia group. Over 55% of AIS Grades A and B cases, 69.7% of MAS level 0 cases and 51.6% of the patients with osteoporosis had sarcopenia. The mean number of comorbidities was 2.7 in the sarcopenia group. Conclusions: Gender, type of injury, presence of multiple comorbidities and age were directly associated with sarcopenia; meanwhile, surprisingly, spasticity level and the presence of immobilization osteoporosis were not.

Xu X., Zhang C., Talifu Z., Liu W., Li Z., Wang X., Du H., Ke H., Yang D., Gao F., Du L., Yu Y., Jing Y., Li J.

AbstractOxidative stress is a frequently occurring pathophysiological feature of spinal cord injury (SCI) and can result in secondary injury to the spinal cord and skeletal muscle atrophy. Studies have reported that glycine and N-acetylcysteine (GlyNAC) have anti-aging and anti-oxidative stress properties; however, to date, no study has assessed the effect of GlyNAC in the treatment of SCI. In the present work, we established a rat model of SCI and then administered GlyNAC to the animals by gavage at a dose of 200 mg/kg for four consecutive weeks. The BBB scores of the rats were significantly elevated from the first to the eighth week after GlyNAC intervention, suggesting that GlyNAC promoted the recovery of motor function; it also promoted the significant recovery of body weight of the rats. Meanwhile, the 4-week heat pain results also suggested that GlyNAC intervention could promote the recovery of sensory function in rats to some extent. Additionally, after 4 weeks, the levels of glutathione and superoxide dismutase in spinal cord tissues were significantly elevated, whereas that of malondialdehyde was significantly decreased in GlyNAC-treated animals. The gastrocnemius wet weight ratio and total antioxidant capacity were also significantly increased. After 8 weeks, the malondialdehyde level had decreased significantly in spinal cord tissue, while reactive oxygen species accumulation in skeletal muscle had decreased. These findings suggested that GlyNAC can protect spinal cord tissue, delay skeletal muscle atrophy, and promote functional recovery in rats after SCI.

Xu X., Du H., Talifu Z., Zhang C., Li Z., Liu W., Liang Y., Xu X., Zhang J., Yang D., Gao F., Du L., Yu Y., Jing Y., Li J.

Skeletal muscle atrophy is a frequent complication after spinal cord injury (SCI) and can influence the recovery of motor function and metabolism in affected patients. Delaying skeletal muscle atrophy can promote functional recovery in SCI rats. In the present study, we investigated whether a combination of body weight support treadmill training (BWSTT) and glycine and N-acetylcysteine (GlyNAC) could exert neuroprotective effects, promote motor function recovery, and delay skeletal muscle atrophy in rats with SCI, and we assessed the therapeutic effects of the double intervention from both a structural and functional viewpoint. We found that, after SCI, rats given GlyNAC alone showed an improvement in Basso–Beattie–Bresnahan (BBB) scores, gait symmetry, and results in the open field test, indicative of improved motor function, while GlyNAC combined with BWSTT was more effective than either treatment alone at ameliorating voluntary motor function in injured rats. Meanwhile, the results of the skeletal muscle myofiber cross-sectional area (CSA), hindlimb grip strength, and acetylcholinesterase (AChE) immunostaining analysis demonstrated that GlyNAC improved the structure and function of the skeletal muscle in rats with SCI and delayed the atrophication of skeletal muscle.

Craven B.C., Cirnigliaro C.M., Carbone L.D., Tsang P., Morse L.R.

Background: The prevention of lower extremity fractures and fracture-related morbidity and mortality is a critical component of health services for adults living with chronic spinal cord injury (SCI). Methods: Established best practices and guideline recommendations are articulated in recent international consensus documents from the International Society of Clinical Densitometry, the Paralyzed Veterans of America Consortium for Spinal Cord Medicine and the Orthopedic Trauma Association. Results: This review is a synthesis of the aforementioned consensus documents, which highlight the pathophysiology of lower extremity bone mineral density (BMD) decline after acute SCI. The role and actions treating clinicians should take to screen, diagnose and initiate the appropriate treatment of established low bone mass/osteoporosis of the hip, distal femur or proximal tibia regions associated with moderate or high fracture risk or diagnose and manage a lower extremity fracture among adults with chronic SCI are articulated. Guidance regarding the prescription of dietary calcium, vitamin D supplements, rehabilitation interventions (passive standing, functional electrical stimulation (FES) or neuromuscular electrical stimulation (NMES)) to modify bone mass and/or anti-resorptive drug therapy (Alendronate, Denosumab, or Zoledronic Acid) is provided. In the event of lower extremity fracture, the need for timely orthopedic consultation for fracture diagnosis and interprofessional care following definitive fracture management to prevent health complications (venous thromboembolism, pressure injury, and autonomic dysreflexia) and rehabilitation interventions to return the individual to his/her pre-fracture functional abilities is emphasized. Conclusions: Interprofessional care teams should use recent consensus publications to drive sustained practice change to mitigate fracture incidence and fracture-related morbidity and mortality among adults with chronic SCI.