Molecular Interactions of Autophagy with the Immune System and Cancer.

Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Autophagy protects against cancer by mediating both innate and adaptive immune responses. Innate immune receptors and lymphocytes (T and B) are modulated by autophagy, which represent innate and adaptive immune responses, respectively. Numerous studies have demonstrated beneficial roles for autophagy induction as well as its suppression of cancer cells. Autophagy may induce either survival or death depending on the cell/tissue type. Radiation therapy is commonly used to treat cancer by inducing autophagy in human cancer cell lines. Additionally, melatonin appears to affect cancer cell death by regulating programmed cell death. In this review, we summarize the current understanding of autophagy and its regulation in cancer.

Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy.

Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

The effects of smartphone use on upper extremity muscle activity and pain threshold.

[Purpose] The purpose of this study was to determine whether muscle activity and pressure-induced pain in the upper extremities are affected by smartphone use, and to compare the effects of phone handling with one hand and with both hands. [Subjects] The study subjects were asymptomatic women 20-22 years of age. [Methods] The subjects sat in a chair with their feet on the floor and the elbow flexed, holding a smartphone positioned on the thigh. Subsequently, the subjects typed the Korean anthem for 3 min, one-handed or with both hands. Each subject repeated the task three times, with a 5-min rest period between tasks to minimize fatigue. Electromyography (EMG) was used to record the muscle activity of the upper trapezius (UT), extensor pollicis longus (EPL), and abductor pollicis (AP) during phone operation. We also used a dolorimeter to measure the pressure-induced pain threshold in the UT. [Results] We observed higher muscle activity in the UT, AP, and EPL in one-handed smartphone use than in its two-handed use. The pressure-induced pain threshold of the UT was lower after use of the smartphone, especially after one-handed use. [Conclusion] Our results show that smartphone operation with one hand caused greater UT pain and induced increased upper extremity muscle activity.

Therapeutic physical exercise in neural injury: friend or foe?

[Purpose] The intensity of therapeutic physical exercise is complex and sometimes controversial in patients with neural injuries. This review assessed whether therapeutic physical exercise is beneficial according to the intensity of the physical exercise. [Methods] The authors identified clinically or scientifically relevant articles from PubMed that met the inclusion criteria. [Results] Exercise training can improve body strength and lead to the physiological adaptation of skeletal muscles and the nervous system after neural injuries. Furthermore, neurophysiological and neuropathological studies show differences in the beneficial effects of forced therapeutic exercise in patients with severe or mild neural injuries. Forced exercise alters the distribution of muscle fiber types in patients with neural injuries. Based on several animal studies, forced exercise may promote functional recovery following cerebral ischemia via signaling molecules in ischemic brain regions. [Conclusions] This review describes several types of therapeutic forced exercise and the controversy regarding the therapeutic effects in experimental animals versus humans with neural injuries. This review also provides a therapeutic strategy for physical therapists that grades the intensity of forced exercise according to the level of neural injury.

Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells.

In Asia, the incidence of colorectal cancer has been increasing gradually due to a more Westernized lifestyle. The aim of study is to determine the interaction between melatonin-induced cell death and cellular senescence. We treated HCT116 human colorectal adenocarcinoma cells with 10 µm melatonin and determined the levels of cell death-related proteins and evaluated cell cycle kinetics. The plasma membrane melatonin receptor, MT1, was significantly decreased by melatonin in a time-dependent manner, whereas the nuclear receptor, RORα, was increased only after 12 hr treatment. HCT116 cells, which upregulated both pro-apoptotic Bax and anti-apoptotic Bcl-xL in the early response to melatonin treatment, activated autophagic as well as apoptotic machinery within 18 hr. Melatonin decreased the S-phase population of the cells to 57% of the control at 48 hr, which was concomitant with a reduction in BrdU-positive cells in the melatonin-treated cell population. We found not only marked attenuation of E- and A-type cyclins, but also increased expression of p16 and p-p21. Compared to the cardiotoxicity of Trichostatin A in vitro, single or cumulative melatonin treatment induced insignificant detrimental effects on neonatal cardiomyocytes. We found that 10 µm melatonin activated cell death programs early and induced G1-phase arrest at the advanced phase. Therefore, we suggest that melatonin is a potential chemotherapeutic agent for treatment of colon cancer, the effects of which are mediated by regulation of both cell death and senescence in cancerous cells with minimized cardiotoxicity.

Melatonin treatment combined with treadmill exercise accelerates muscular adaptation through early inhibition of CHOP-mediated autophagy in the gastrocnemius of rats with intra-articular collagenase-induced knee laxity.

The purpose of this study was to determine the effects of melatonin intervention on gastrocnemius remodeling in rats with collagenase-induced knee instability. Type VII collagenase was injected into the right knee to induce joint laxity with cartilage destruction. Melatonin (MT; 10 mg/kg) injection was performed twice daily subcutaneously, and treadmill exercise (Ex; 11 m/min) was conducted for 1 hr/day at a frequency of 5 days/wk for 4 wks. The gastrocnemius mass, which was reduced with collagenase injection only (Veh), was increased with collagenase injection with melatonin treatment with and without exercise in the early phase, and the mass in both limbs was significantly different in the Veh compared with the MT group. However, there was an increase in the relative muscle weight to body weight ratio in the Veh group at the advanced stage. Insulin-like growth factor receptor (IGF-IR) was downregulated in the Veh group, whereas IGF-IR was upregulated in the MT and MT + Ex groups. Joint laxity induced enhancement of autophagic proteolysis (LC3 II) in the muscle, which was recovered to values similar to those in the normal control group (Con) compared with those in the MT and MT+Ex groups. Although intra-articular collagenase increased the total C/EBP homology protein (CHOP) levels at 1 wk and decreased them at 4 wks in the Veh group, CHOP in the nucleus was upregulated continuously. Prolonged melatonin treatment with and without exercise intervention suppressed nuclear localization of ATF4 and CHOP with less activation of caspase-3, at the advanced phase. Moreover, the interventions promoted the expression of myosin heavy chain (MHC) isoforms under the control of myogenin. Concomitant with a beneficial effect of melatonin with and without exercise, step length of the saline-injected limb and the collagenase-injected supporting side was maintained at values similar to those in control rats. Taken together, the findings demonstrate that melatonin with and without exercise accelerate remodeling of the gastrocnemius through inhibition of nuclear CHOP in rats with collagenase-induced knee instability.

Salutary effects of melatonin combined with treadmill exercise on cartilage damage.

Osteoarthritis (OA) is a major cause of disability in the adult population. The purpose of this study was to evaluate the effects of melatonin with graded dosage on extracellular matrix synthesis and cellular death in response to cartilage damage in vitro and in vivo. TNF-α reduced the viability of primary cultured chondrocytes and extracellular matrix protein, but melatonin at concentrations of 1 µm and 1 nm restored them. Rats with knee instability induced by intra-articular collagenase were used for the in vivo study. Joint parameters were significantly augmented in the collagenase injection-only group but not in the melatonin-alone or melatonin+exercise groups, as cartilage degeneration progressed. Serum TNF-α and IL-6 were upregulated by collagenase injection, which was attenuated by melatonin with and without exercise in the early phase. TGF-ß1 mRNA was either conserved or enhanced by melatonin with and without exercise at the early phase. In particular, melatonin combined with exercise dramatically decreased the expression of not only catabolic mediators but also cellular death markers with lower mineralization. At the advanced phase, prolonged melatonin treatment promoted mineralization through caspase-3-mediated chondrocyte apoptosis. However, co-intervention induced extracellular matrix remodeling through increases in IL-6, EPAS-1, and MMP-13. Reconstructed micro-CT images showed that collagenase injection induced subchondral bone erosion, formation of parameniscal osteophytes, and reduction of trabecular bone thickness regardless of the intervention, which was minimized by combined intervention. In conclusion, we suggest that melatonin with treadmill exercise may have both preventive and synergistic effects on rescue from cartilage degeneration and is more effective in the initial phase.

Beneficial effects of melatonin combined with exercise on endogenous neural stem/progenitor cells proliferation after spinal cord injury.

Endogenous neural stem/progenitor cells (eNSPCs) proliferate and differentiate into neurons and glial cells after spinal cord injury (SCI). We have previously shown that melatonin (MT) plus exercise (Ex) had a synergistic effect on functional recovery after SCI. Thus, we hypothesized that combined therapy including melatonin and exercise might exert a beneficial effect on eNSPCs after SCI. Melatonin was administered twice a day and exercise was performed on a treadmill for 15 min, six days per week for 3 weeks after SCI. Immunohistochemistry and RT-PCR analysis were used to determine cell population for late response, in conjunction with histological examination and motor function test. There was marked improvement in hindlimb function in SCI+MT+Ex group at day 14 and 21 after injury, as documented by the reduced size of the spinal lesion and a higher density of dendritic spines and axons; such functional improvements were associated with increased numbers of BrdU-positive cells. Furthermore, MAP2 was increased in the injured thoracic segment, while GFAP was increased in the cervical segment, along with elevated numbers of BrdU-positive nestin-expressing eNSPCs in the SCI+MT+Ex group. The dendritic spine density was augmented markedly in SCI+MT and SCI+MT+Ex groups.These results suggest a synergistic effect of SCI+MT+Ex might create a microenvironment to facilitate proliferation of eNSPCs to effectively replace injured cells and to improve regeneration in SCI.

Beneficial effects of endogenous and exogenous melatonin on neural reconstruction and functional recovery in an animal model of spinal cord injury.

The purpose of this study was to investigate the beneficial effects of endogenous and exogenous melatonin on functional recovery in an animal model of spinal cord injury (SCI). Eight-week-old male Sprague-Dawley (SD, 250-260 g) rats were used for contusion SCI surgery. All experimental groups were maintained under one of the following conditions: 12/12-hr light/dark (L/D) or 24:0-hr constant light (LL). Melatonin (10 mg/kg) was injected subcutaneously for 4 wk, twice daily (07:00, 19:00). Locomotor recovery, inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein gene expression, and muscle atrophy-related genes, including muscle atrophy F-box (MAFbx) and muscle-specific ring-finger protein 1 (MuRF1) gene expression were evaluated. Furthermore, autophagic signaling such as Beclin-1 and LC3 protein expression was examined in the spinal cord and in skeletal muscle. The melatonin treatment resulted in increased hind-limb motor function and decreased iNOS mRNA expression in the L/D condition compared with the LL condition (P < 0.05), indicating that endogenous melatonin had neuroprotective effects. Furthermore, the MAFbx, MuRF1 mRNA level, and converted LC3 II protein expression were decreased in the melatonin-treated SCI groups under the LL (P < 0.05), possibly in response to the exogenous melatonin treatment. Therefore, it seems that both endogenous and exogenous melatonin contribute to neural recovery and to the prevention of skeletal muscle atrophy, promoting functional recovery after SCI. Finally, this study supports the benefit of endogenous melatonin and use of exogenous melatonin as a therapeutic intervention for SCI.

Synergistic effect of melatonin on exercise-induced neuronal reconstruction and functional recovery in a spinal cord injury animal model.

Nitric oxide (NO) may aggravate neuronal damage after spinal cord injury (SCI). We hypothesized that NO produced by inducible nitric oxide synthase (iNOS) accelerates secondary damage to spinal tissue, which may be reversed by the neuroprotectant, melatonin. This study investigated the effects of combination therapy with melatonin (10 mg/kg) and exercise (10 m/min) on recovery from SCI caused by contusion. We examined locomotor recovery, iNOS gene expression, autophagic and apoptotic signaling, including Beclin-1, LC3, p53 and IKKalpha protein expression and histological alterations in the ventral horn of the spinal cord. Melatonin in combination with exercise resulted in significantly increased hindlimb movement (P < 0.05), a reduced level of iNOS mRNA (P < 0.05) and more motor neurons in the ventral horn, versus control SCI and SCI plus exercise alone, with no effect on the other signaling molecules examined. This study shows that combined therapy with melatonin and exercise reduces the degree of secondary damage associated with SCI in rats and supports the possible use of melatonin in combination with exercise to reduce the side effects related to exercise-induced fatigue and impairment.

Dermatomyositis, complicated with pneumomediastinum, successfully treated with cyclosporine A: a case report and review of literature.

We report a rare case of patient with dermatomyositis (DM) who developed spontaneous pneumomediastinum (PnM) and subcutaneous emphysema. She was successfully treated with oral prednisolone and cyclosporine A (CsA). We reviewed the cases of PnM in patients with DM treated with CsA. A review of four previously reported cases revealed that treatment with systemic glucocorticoid and CsA was effective for the DM and PnM. We indicate that initial and early treatment of the patients with DM and PnM with CsA enabled rapid tapering of the dose of glucocorticoid and improved the disease.

Conditional Controlled Light/Dark Cycle Influences Exercise-Induced Benefits in a Rat Model with Osteoarthritis: In Vitro and In Vivo Study.

Physical exercise has long been recommended as a treatment for osteoarthritis (OA), though its effects vary based on the exercise protocol. Here, we examined whether environmental lighting conditions influence the anti-inflammatory benefits of exercise in a rat model of OA. Moderate-intensity treadmill exercise (Ex) was performed for six weeks under a 12:12 h light/dark (L/D) cycle, and compared against rats housed in a 24 h continuous light (L/L) environment. L/L conditions were associated with serological changes shortly after OA induction, which exacerbated the inflammatory microenvironment in the joint. Differentiation capacity was also impaired in bone precursor cells isolated from normal rats maintained under L/L conditions, despite elevated inflammatory responses. Exercise training under L/L conditions led to increased corticosterone levels in the blood, which exacerbated the progression of cartilaginous and synovial lesions. Osteoporotic phenomena were also observed in exercise-trained rats maintained under L/L conditions, along with inflammation-induced catabolism in the gastrocnemius muscle. Aberrant light/dark cycle conditions were also found to be associated with suppression of splenic Cry1 expression in exercise-trained rats, leading to dysregulation of immune responses. Taken together, these data suggest that lighting condition may be an important environmental factor influencing the exercise-induced benefits on OA.

Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent?

Osteoarthritis (OA), the most common form of arthritis, may be triggered by improper secretion of circadian clock-regulated hormones, such as melatonin, thyroid-stimulating hormone (TSH), or cortisol. The imbalance of these hormones alters the expression of pro-inflammatory cytokines and cartilage degenerative enzymes in articular cartilage, resulting in cartilage erosion, synovial inflammation, and osteophyte formation, the major hallmarks of OA. In this review, we summarize the effects of circadian melatonin, TSH, and cortisol on OA, focusing on how different levels of these hormones affect OA pathogenesis and recovery with respect to the circadian clock. We also highlight the effects of melatonin, TSH, and cortisol at different concentrations both in vivo and in vitro, which may help to elucidate the relationship between circadian hormones and OA.

Elevated Serum Melatonin under Constant Darkness Enhances Neural Repair in Spinal Cord Injury through Regulation of Circadian Clock Proteins Expression.

We investigated the effects of environmental lighting conditions regulating endogenous melatonin production on neural repair, following experimental spinal cord injury (SCI). Rats were divided into three groups randomly: the SCI + L/D (12/12-h light/dark), SCI + LL (24-h constant light), and SCI + DD (24-h constant dark) groups. Controlled light/dark cycle was pre-applied 2 weeks before induction of spinal cord injury. There was a significant increase in motor recovery as well as body weight from postoperative day (POD) 7 under constant darkness. However, spontaneous elevation of endogenous melatonin in cerebrospinal fluid was seen at POD 3 in all of the SCI rats, which was enhanced in SCI + DD group. Augmented melatonin concentration under constant dark condition resulted in facilitation of neuronal differentiation as well as inhibition of primary cell death. In the rostrocaudal region, elevated endogenous melatonin concentration promoted neural remodeling in acute phase including oligodendrogenesis, excitatory synaptic formation, and axonal outgrowth. The changes were mediated via NAS-TrkB-AKT/ERK signal transduction co-regulated by the circadian clock mechanism, leading to rapid motor recovery. In contrast, exposure to constant light exacerbated the inflammatory responses and neuroglial loss. These results suggest that light/dark control in the acute phase might be a considerable environmental factor for a favorable prognosis after SCI.

Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model.

Autism spectrum disorder (ASD) is induced by complex hereditary and environmental factors. However, the mechanisms of ASD development are poorly understood. The purpose of this study was to identify standard indicators of this condition by comparing clinical, pathophysiological, and neurobehavioral features in an autism-like animal model. A total of 22 male Sprague-Dawley rats were randomly divided into control and 500 mg/kg propionic acid (PPA)-treated groups. Rats were subjected to behavioral tests, gene expression analyses, and histological analyses to detect pathophysiological and neurobehavioral alterations. Exploratory activity and non-aggressive behavior were significantly reduced in PPA-treated rats, whereas enhanced aggressive behavior during adjacent interactions was observed on day 14 after PPA administration. To evaluate gene expression after PPA administration, we analyzed hippocampal tissue using reverse transcription PCR. Glial fibrillary acidic protein was augmented in the PPA-treated group on day 14 after appearance of ASD-like behaviors by PPA administration, whereas octamer-binding transcription factor 4 expression was significantly decreased in the PPA-treated group. Histological evaluation revealed significantly reduced diameter and layer thickness of granule cells in PPA-treated rats compared with control rats. We conclude that PPA administration induced abnormal neural cell organization, which may have led to autism-like neurobehaviors, including increased aggressive behavior, reduced exploratory activity, and isolative and passive behaviors.

Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee.

Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-α were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens. Nanomolar doses of melatonin restored the expression of clock-controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype.

NAMPT enzyme activity regulates catabolic gene expression in gingival fibroblasts during periodontitis.

Periodontal disease is one of the most prevalent chronic disorders worldwide. It is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss. Here, we focused on the role of adipokines, which are locally expressed by periodontal tissues, in the regulation of catabolic gene expression leading to periodontal inflammation. The expression of the nicotinamide phosphoribosyltransferase (NAMPT) adipokine was dramatically increased in inflamed human and mouse gingival tissues. NAMPT expression was also increased in lipopolysaccharide- and proinflammatory cytokine-stimulated primary cultured human gingival fibroblasts (GF). Adenovirus-mediated NAMPT (Ad-Nampt) overexpression upregulated the expression and activity of COX-2, MMP1 and MMP3 in human GF. The upregulation of IL-1ß- or Ad-Nampt-induced catabolic factors was significantly abrogated by the intracellular NAMPT (iNAMPT) inhibitor, FK866 or by the sirtuin (SIRT) inhibitor, nicotinamide (NIC). Recombinant NAMPT protein or extracellular NAMPT (eNAMPT) inhibition using a blocking antibody did not alter NAMPT target gene expression levels. Moreover, intragingival Ad-Nampt injection mediated periodontitis-like phenotypes including alveolar bone loss in mice. SIRT2, a part of the SIRT family, was positively associated with NAMPT actions in human GF. Furthermore, in vivo inhibition of the NAMPT-NAD+-SIRT axis by NIC injection in mice ameliorated the periodontal inflammation and alveolar bone erosion caused by intragingival injection of Ad-Nampt. Our findings indicate that NAMPT is highly upregulated in human GF, while its enzymatic activity acts as a crucial mediator of periodontal inflammation and alveolar bone destruction via regulation of COX-2, MMP1, and MMP3 levels.

Benefits of Physical Exercise for Individuals with Fragile X Syndrome in Humans.

Fragile X syndrome (FXS) is the most common known genetic cause of autism spectrum disorder, and is also linked to other neurologic and psychiatric disorders. The purpose of this review article is to examine a variety of recent studies on the correlation between physical exercise and autistic behavior in individuals with fragile X syndrome. Additionally, we discuss promising approaches for further investigation of the benefits of physical exercise for autism spectrum disorder (ASD) patients. A systematic search of the PubMed digital library database for pertinent articles published from 1995 to 2011 was conducted. Individuals with ASD who experience exercise tend to exhibit improvement in physical function. In addition, exercise promotes neurotrophic factors and boosts the growth of new brain cells. The collected review articles describe how physical exercise has particular effects on stereotypic behavior and cognition among ASD patients. Finally, physical exercise may benefit patients with autism spectrum disorder through the improvement of muscular strength for increased physical capability.

Comparison of surgical methods of transient middle cerebral artery occlusion between rats and mice.

Rodent models of focal cerebral ischemia that do not require craniotomy have been developed by intraluminal suture middle cerebral artery occlusion (MCAo). Mouse MCAo models have been widely used and extended to genetic studies of cell death or recovery mechanisms. Therefore, we compared surgery-related parameters and techniques between such rats and mice. In rodent MCAo models, has to be considered body temperature during the operative period, as well as the need for the use of a standardized tip in terms of the outer diameter of probes. Induction of focal cerebral ischemia was measured by neurological dysfunction parameters. Our methods could induce stable moderate-severity ischemic brain injury models and histological alteration at 24 hr after MCAo surgery. Moreover approximately 80% (rats) and 85% (mice) survival ratios were shown indicating with model engineering success. Finally, we described and compared major parameters between rats and mice, including probe size, thread insert length, operation and occlusion periods, and differences in the procedures.

Differential expression of caveolins and myosin heavy chains in response to forced exercise in rats.

Exercise training can improve strength and lead to adaptations in the skeletal muscle and nervous systems. Skeletal muscles can develop into two types: fast and slow, depending on the expression pattern of myosin heavy chain (MHC) isoforms. Previous studies reported that exercise altered the distribution of muscle fiber types. It is not currently known what changes in the expression of caveolins and types of muscle fiber occur in response to the intensity of exercise. This study determined the changes in expression of caveolins and MHC type after forced exercise in muscular and non-muscular tissues in rats. A control (Con) group to which forced exercise was not applied and an exercise (Ex) group to which forced exercise was applied. Forced exercise, using a treadmill, was introduced at a speed of 25 m/min for 30 min, 3 times/day (07:00, 15:00, 23:00). Homogenized tissues were applied to extract of total RNA for further gene analysis. The expression of caveolin-3 and MHC2a in the gastrocnemius muscle of female rats significantly increased in the Ex group compared with the Con group (P<0.05). Furthermore, in the gastrocnemius muscle of male rats, the expression of MHC2x was significantly different between the two groups (P<0.05). There was an increased expression in caveolin-3 and a slightly decreased expression in TGFß-1 in muscular tissues implicating caveolin-3 influences the expression of MHC isoforms and TGFß-1 expression. Eventually, it implicates that caveolin-3 has positive regulatory function in muscle atrophy induced by neural dysfunction with spinal cord injury or stroke.