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Muscle fiber mitochondria in response to disuse (red colored mitochondria) and exercise (blue colored mitochondria). Disuse of skeletal muscle from immobilization or unloading mechanistically triggers downstream regulation of mitochondrial density and activity. Disuse atrophy is associated with reduced numbers of mitochondria, changes in mitochondrial morphology and increased mitochondrial ROS production. AMPK (adenosine monophosphate kinase), (Mfn-2) Mitofusin-2, and SIRT1 (Sirtuin 1) respond to nutrient availability in a cell and regulate the metabolism, gene expression, and mitochondrial function. AMPK adenosine monophosphate kinase, SIRT1 Sirtuin 1, Mfn2 Mitofusin-2
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Mitochondria are responsible for aerobic respiration and large-scale ATP production in almost all cells of the body. Their function is decreased in many neurodegenerative and cardiovascular disease states, in metabolic disorders such as type II diabetes and obesity, and as a normal component of aging. Disuse of skeletal muscle from immobilization o...
Citations
... Furthermore, different studies indicate that muscle tissues of MG patients show mitochondrial dysfunction and low energy levels [59,60]. Increasing production of ROS due to mitochondrial dysfunction triggers activation of autophagy resulting in the induction of catabolism and reduced protein synthesis in the skeletal muscles [61]. There is a special connection between autophagy and mitochondrial dysfunction, as activated autophagy prevents the development and progression of mitochondrial dysfunction in different diseases [62]. ...
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) that results from autoantibodies against nicotinic acetylcholine receptors (nAchRs) at NMJs. These autoantibodies are mainly originated from autoreactive B cells that bind and destroy nAchRs at NMJs preventing nerve impulses from activating the end-plates of skeletal muscle. Indeed, immune dysregulation plays a crucial role in the pathogenesis of MG. Autoreactive B cells are increased in MG due to the defect in the central and peripheral tolerance mechanisms. As well, autoreactive T cells are augmented in MG due to the diversion of regulatory T (Treg) cells or a defect in thymic anergy leading to T cell-mediated autoimmunity. Furthermore, macroautophagy/autophagy, which is a conserved cellular catabolic process, plays a critical role in autoimmune diseases by regulating antigen presentation, survival of immune cells and cytokine-mediated inflammation. Abnormal autophagic flux is associated with different autoimmune disorders. Autophagy regulates the connection between innate and adaptive immune responses by controlling the production of cytokines and survival of Tregs. As autophagy is involved in autoimmune disorders, it may play a major role in the pathogenesis of MG. Therefore, this mini-review demonstrates the potential role of autophagy and autophagy activators in MG.Abbreviations: Ach, acetylcholine; Breg, regulatory B; IgG, immunoglobulin G; MG, myasthenia gravis; NMJ, neuromuscular junction; ROS, reactive oxygen species; Treg, regulatory T; Ubl, ubiquitin-like.
... We also determined the T-AOC as a representative indicator of the antioxidant capacity of skeletal muscle and found that at 4 weeks, T-AOC was significantly decreased in SCI rats relative to that in the control and GlyNAC+SCI groups. SCI leads to ROS accumulation in skeletal muscle [40], resulting in oxidative injury, a key contributing factor to skeletal muscle atrophy [41]. The results of the immunofluorescence staining in the gastrocnemius muscle at 8 weeks showed that ROS accumulation and release increased after SCI, the ROS-positive cell rate increased significantly, the percentage of ROS-positive area also increased, and the immunofluorescence intensity was significantly enhanced. ...
Oxidative 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.
... Autophagy is the process of combining damaged organelles or denatured proteins with lysosomes for selfdegradation [47]. Mitophagy refers to a selective form of autophagy that functions to maintain mitochondrial homeostasis by selectively eliminating damaged or surplus mitochondria [48]. ...
Spinal cord injury (SCI) is a serious central nervous system (CNS) injury disease related to hypoxia-ischemia and inflammation. It is characterized by excessive reactive oxygen species (ROS) production, oxidative damage to nerve cells, and mitochondrial dysfunction. Mitochondria serve as the primary cellular origin of ROS, wherein the electron transfer chain complexes within oxidative phosphorylation frequently encounter electron leakage. These leaked electrons react with molecular oxygen, engendering the production of ROS, which culminates in the occurrence of oxidative stress. Oxidative stress is one of the common forms of secondary injury after SCI. Mitochondrial oxidative stress can lead to impaired mitochondrial function and disrupt cellular signal transduction pathways. Hence, restoring mitochondrial electron transport chain (ETC), reducing ROS production and enhancing mitochondrial function may be potential strategies for the treatment of SCI. This article focuses on the pathophysiological role of mitochondrial oxidative stress in SCI and evaluates in detail the neuroprotective effects of various mitochondrial-targeted antioxidant therapies in SCI, including both drug and non-drug therapy. The objective is to provide valuable insights and serve as a valuable reference for future research in the field of SCI.
... For example, it has been found that protein expression and mitochondrial function in skeletal muscle are impaired after SCI [60]. The subsequent increase in the release of ROS leads to the ubiquitination and degradation of proteins in skeletal muscle and results in damage to the structure of the motor endplate, motor endplate dysfunction, accumulation of fat in the skeletal muscle, type II diabetes, and cardiovascular disease, among other conditions [61,62]. This highlights the importance of determining the underlying causes of skeletal muscle atrophy after SCI and identifying strategies for its prevention. ...
... Skeletal muscle after SCI is currently treated with exercise training, physical therapy, and testosterone therapy, among other therapeutic options, but each has its advantages and disadvantages in delaying skeletal muscle atrophy [61,63]. Although many studies, both basic and clinical, have been conducted relating to the treatment of post-SCI skeletal muscle atrophy, no drug that can counteract skeletal muscle atrophy after severe SCI has yet been approved [4]. ...
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.
... Muscle atrophy following SCI includes a decrease in muscle cross-sectional area from a loss in the total number of muscle fibres and shrinking in size of remaining fibres from a combination of disuse and denervation (Otzel et al. 2021). In addition to general muscle atrophy, individuals with SCI experience mitochondrial dysfunction and a conversion of slow-oxidative muscle fibres to fast-glycolytic muscle fibres, generally increasing the fatiguability of muscle tissue due to changes in muscle contractile properties Gorgey et al. 2019). ...
Persons with spinal cord injury (SCI) experience gains in fitness, physical and mental health from regular participation in exercise and physical activity. Due to changes in physiological function of the cardiovascular, nervous, and muscular systems, general population physical activity guidelines and traditional exercise prescription methods are not appropriate for the SCI population. Exercise guidelines specific to persons with SCI recommend progressive training beginning at 20 min of moderate to vigorous intensity aerobic exercise twice per week transitioning to 30 min three times per week, with strength training of the major muscle groups two times per week. These population-specific guidelines were designed considering the substantial barriers to physical activity for persons with SCI and can be used to frame an individual exercise prescription. Rating of perceived exertion (i.e., perceptually regulated exercise) is a practical way to indicate moderate to vigorous intensity exercise in community settings. Adapted exercise modes include arm cycle ergometry, hybrid arm–leg cycling, and recumbent elliptical equipment. Body weight-supported treadmill training and other rehabilitation modalities may improve some aspects of health and fitness for people with SCI if completed at sufficient intensity. Disability-specific community programs offer beneficial opportunities for persons with SCI to experience quality exercise opportunities but are not universally available.
... Despite these factors, obesity is still more prevalent among persons with chronic SCI compared to able-bodied persons [8][9][10][11][12]. Persons with chronic SCI also have an increased risk for obesity-related cardiometabolic diseases [13], including dyslipidemia [14][15][16], glucose intolerance and diabetes mellitus [15,[17][18][19][20][21][22][23], central obesity [24][25][26][27], systemic inflammation, [19,[28][29][30][31] and mitochondrial dysfunction [32,33]. ...
Background:
Changes in body composition and dietary intake occur following spinal cord injury (SCI). The Geometric Framework for Nutrition (GFN) is a tool that allows the examination of the complex relationships between multiple nutrition factors and health parameters within a single model. This study aimed to utilize the GFN to examine the associations between self-reported macronutrient intakes and body composition in persons with chronic SCI.
Methods:
Forty-eight individuals with chronic SCI were recruited. Participants completed and returned 3- or 5-day self-reported dietary recall sheets. The mean macronutrient masses (g) for fats, proteins, and carbohydrates were analyzed. Circumferential anthropometric measures, dual-energy x-ray absorptiometry (DXA), and magnetic resonance imaging (MRI) were used to assess body composition.
Results:
Associations between all the circumferential anthropometric measures and carbohydrates were observed (p ≤ 0.01). Among the MRI measures, only significant associations between subcutaneous adipose tissue and protein*carbohydrate (p = 0.0402) as well as carbohydrates (p = 0.0046) were identified. Carbohydrates were negatively associated with total percent fat mass (%total FM; p = 0.0017), total fat mass (Total FM [g]; p = 0.0042), trunk percent fat mass (%trunk FM; p = 0.0095), trunk fat mass (Trunk FM [g]; (p = 0.0086), lower extremity percent fat mass (%LE FM; p = 0.0121), and lower extremity fat mass (LE FM [g]; p = 0.0211).
Conclusions:
Carbohydrates appear to play an important role in body composition among individuals with SCI. Higher carbohydrate intake was associated with lower fat mass. Additional research is needed to determine how carbohydrate intake influences body composition and cardiometabolic health after SCI.
... In addition, from the time of injury and in the long term, there is a decrease in blood flow to the regions below the lesion [98,99]. The muscle tissue in these patients shows a decrease in the radius of the fibers, loss of nuclei that alters regenerative capacity and a decreased number of mitochondria and their functionality [100,101]. In addition, within months, the change from type I fibers begins to occur until, within years, type IIx fibers predominate [17]. ...
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.
... Additionally, Hedges et al. did not examine the individual respiration rates for complex II and complex IV. Following SCI, several profound physiological changes are observed, including long-term negative effects on mitochondrial regulation and activity [70]. While, Hedges et al. enrolled homogenous, able-bodied young male participants, the current study successfully recruited a heterogenous group of individuals with chronic SCI. ...
... PBMCs) should increase in response to physical training is less clear. The mitochondrial capacity of PBMCs appear to be less responsive to change in the direction of an increase in respiratory capacity following acute high-intensity training [21], but may be more susceptible to become impaired in chronic diseases states that consist of systemic factors including inflammation, oxidative stress, and/or metabolic syndrome that are evident in individuals with SCI [70,73,74]. Therefore, PBMCs may still serve as a useful biomarker of muscle mitochondrial function in individuals with SCI, a pathological population with chronically compromised mitochondrial respiratory capacity compared to their able-bodied counterparts. ...
Purpose
Muscle biopsies are the gold standard to assess mitochondrial respiration; however, biopsies are not always a feasible approach in persons with spinal cord injury (SCI). Peripheral blood mononuclear cells (PBMCs) and near-infrared spectroscopy (NIRS) may alternatively be predictive of mitochondrial respiration. The purpose of the study was to evaluate whether mitochondrial respiration of PBMCs and NIRS are predictive of respiration of permeabilized muscle fibers after SCI.
Methods
Twenty-two individuals with chronic complete and incomplete motor SCI between 18–65 years old were recruited to participate in the current trial. Using high-resolution respirometry, mitochondrial respiratory capacity was measured for PBMCs and muscle fibers of the vastus lateralis oxidizing complex I, II, and IV substrates. NIRS was used to assess mitochondrial capacity of the vastus lateralis with serial cuff occlusions and electrical stimulation.
Results
Positive relationships were observed between PBMC and permeabilized muscle fibers for mitochondrial complex IV (r = 0.86, P < 0.0001). Bland-Altman displayed agreement for complex IV (MD = 0.18, LOA = -0.86 to 1.21), between PBMCs and permeabilized muscles fibers. No significant relationships were observed between NIRS mitochondrial capacity and respiration in permeabilized muscle fibers.
Conclusions
This is the first study to explore and support the agreement of less invasive clinical techniques for assessing mitochondrial respiratory capacity in individuals with SCI. The findings will assist in the application of PBMCs as a viable alternative for assessing mitochondrial health in persons with SCI in future clinical studies.
... It is known that any loss in symmetry in either the neural or biomechanical arrangement would generate discrepancies between the two systems. Amputation or immobilization of a limb, for instance, will cause strong reorganization in various parts of the neural system (Bramati et al., 2019;Makin and Flor, 2020;Conboy et al., 2021;Raffin, 2021), while an accidental or pathological neural asymmetry will trigger plasticity in both the neural and biomechanical (e.g., muscle; Gorgey et al., 2019) systems. In the following, we will only review studies regarding neural plasticity and behavioral adaptation in response to damage-induced central asymmetry. ...
In most vertebrates, posture and locomotion are achieved by a biomechanical apparatus whose effectors are symmetrically positioned around the main body axis. Logically, motor commands to these effectors are intrinsically adapted to such anatomical symmetry, and the underlying sensory-motor neural networks are correspondingly arranged during central nervous system (CNS) development. However, many developmental and/or life accidents may alter such neural organization and acutely generate asymmetries in motor operation that are often at least partially compensated for over time. First, we briefly present the basic sensory-motor organization of posturo-locomotor networks in vertebrates. Next, we review some aspects of neural plasticity that is implemented in response to unilateral central injury or asymmetrical sensory deprivation in order to substantially restore symmetry in the control of posturo-locomotor functions. Data are finally discussed in the context of CNS structure-function relationship.
... The effect of LEMS improvement arises from FES-cycling training. NMES and FES training have been reported to increase muscle mass, mitochondrial oxidative enzyme activities, plasma glucose level, and circulating insulin (de Freitas et al., 2018;Gorgey et al., 2019). However, detailed discussion of underlying mechanism is beyond the scope of this study. ...
Background: To investigate the effect and dose-response of functional electrical stimulation cycling (FES-cycling) training on spasticity in the individuals with spinal cord injury (SCI).
Method: Five electronic databases [PubMed, Scopus, Medline (Proquest), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL)] were searched before September 2021. The human trials and studies of English language were only included. Two authors independently reviewed and extracted the searched studies. The primary outcome measure was spasticity assessed by Modified Ashworth Scale or Ashworth Scale for lower limbs. The secondary outcome measures were walking abilities, such as 6 Min Walk Test (6MWT), Timed Up and Go (TUG), and lower limbs muscle strength (LEMS). A subgroup analysis was performed to investigate the efficacious threshold number of training sessions. A meta-regression analysis was used to examine the linear relationship between the training sessions and the effect on spasticity.
Results: A total of 764 studies were identified. After screening, 12 selected studies were used for the qualitative synthesis, in which eight of them were quantitatively analyzed. Eight studies included ninety-nine subjects in total with SCI (male: female = 83:16). The time since injury was from less than 4 weeks to 17 years. The age ranged from 20 to 67 years. American Spinal Injury Association (ASIA) impairment level of the number of participants was 59 for ASIA A, 11 for ASIA B, 18 for ASIA C, and 11 for ASIA D. There were 43 subjects with tetraplegia and 56 subjects with paraplegia. Spasticity decreased significantly (95% CI = − 1.538 to − 0.182, p = 0.013) in favor of FES-cycling training. The walking ability and LEMS also improved significantly in favor of FES-cycling training. The subgroup analysis showed that spasticity decreased significantly only in more than 20 training sessions (95% CI = − 1.749 to − 0.149, p = 0.020). The meta-regression analysis showed training sessions and spasticity were not significantly associated (coefficient = − 0.0025, SE = 0.0129, p = 0.849, R² analog = 0.37).
Conclusion: Functional electrical stimulation-cycling training can improve spasticity, walking ability, and the strength of the lower limbs in the individuals with SCI. The number of training sessions is not linearly related to the decrease of spasticity. Twenty sessions of FES-cycling training are required to obtain the efficacy to decrease spasticity.
