This study aims to explore the role and mechanism of CXC chemokine receptor 3 (CXCR3) in cisplatin-induced skeletal muscle atrophy. Wild-type mice were divided into two groups: cisplatin group and control group (treated by normal saline). The results showed that, compared to the control group, the expression levels of CXCR3 mRNA and protein were significantly up-regulated in the skeletal muscle of the cisplatin group, suggesting that CXCR3 may play an important role in the model of cisplatin-induced skeletal muscle atrophy. To further investigate its role and potential mechanisms, CXCR3 knockout mice and wild-type mice were treated with cisplatin to induce skeletal muscle atrophy. The results revealed that CXCR3 knockout not only failed to alleviate cisplatin-induced skeletal muscle atrophy, but also further reduced body weight, skeletal muscle mass, and muscle fiber cross-sectional area. Further analysis showed that, in the cisplatin-induced muscle atrophy model, CXCR3 knockout significantly up-regulated the expression levels of E3 ubiquitin ligases in skeletal muscle and down-regulated the expression levels of myogenic regulatory factors. To explore the molecular mechanism by which CXCR3 gene deletion exacerbated cisplatin-induced skeletal muscle atrophy, transcriptomic sequencing was performed on the atrophied skeletal muscles of wild-type and CXCR3 knockout mice. The results showed that, compared to wild-type mice, 14 genes were significantly up-regulated and 12 genes were significantly down-regulated in the skeletal muscle of CXCR3 knockout mice. Gene set enrichment analysis (GSEA) revealed a significant enrichment of genes related to fatty acid β-oxidation. Quantitative real-time PCR validation results were consistent with the transcriptomic sequencing results. These findings suggest that CXCR3 may counteract cisplatin-induced skeletal muscle atrophy by up-regulating E3 ubiquitin ligases, down-regulating myogenic regulatory factors, and enhancing the recruitment of fatty acid β-oxidation-related genes.
Animals ; Cisplatin/adverse effects* ; Muscular Atrophy/physiopathology* ; Mice ; Receptors, CXCR3/metabolism* ; Ubiquitin-Protein Ligases/metabolism* ; Mice, Knockout ; Oxidation-Reduction ; Fatty Acids/metabolism* ; Muscle, Skeletal/metabolism* ; Mice, Inbred C57BL ; Male

OBJECTIVE: To investigate the therapeutic effects of massage on denervated skeletal muscle atrophy in rats and its mechanism. METHODS: Forty-eight male SD rats were randomly divided into model group (n=24) and massage group (n=24). Gastrocnemius muscle atrophy model was established by transecting the right tibial nerve of rat. On the second day after operation, the gastrocnemius muscle of the rats in the massage group was given manual intervention and the model group was not intervened. Six rats were sacrificed at the four time points of 0 d, 7 d, 14 d and 21 d. The gastrocnemius of the rats were obtained and measured the wet mass ratio after weighing. Cross-sectional area and diameter of the muscle fiber were measured after HE staining. The relative expressions of miR-23a, Akt, MuRF1 and MAFbx mRNA were tested with qPCR. RESULTS: Compared with 0 d, the wet weight ratio, cross-sectional area and diameter of gastrocnemius muscle showed a progressive decline in the model group and massage group. The wet weight ratio, cross-sectional area and diameter of gastrocnemius muscle in the massage group were higher than those in the model group on 7 d, 14 d and 21 d (P＜0.05, P＜0.01). Compared with 0 d, the expressions of MuRF1, MAFbx and Akt mRNA were increased first and then were decreased in the model group and massage group. The expression of MuRF1 mRNA in massage group was lower than that in model group on 7 d and 21 d (P＜0.05, P＜0.01). The expression of MAFbx mRNA in massage group was lower than that in model group on 7 d, 14 d and 21 d (P＜0.01, P＜0.05, P＜0.01). The expression of Akt mRNA in massage group was higher than that in model group on 7 d, 14 d and 21 d (P＜0.05, P＜0.01). Compared with 0 d, the expression of miR-23a mRNA was increased in the model group and massage group on 21 d, and the expression of miR-23a mRNA in massage group was higher than that in model group (P＜ 0.05). CONCLUSION Massage can delay the atrophy of denervated skeletal muscle. The mechanism may be related to up-regulation of the expression of miR-23a and Akt mRNA, down-regulation of the expressions of MuRF1 and MAFbx mRNA, inhibition of protein degradation rate, and reduction of skeletal muscle protein degradation.
Animals ; Male ; Massage ; MicroRNAs ; metabolism ; Muscle Fibers, Skeletal ; Muscle Proteins ; metabolism ; Muscle, Skeletal ; physiopathology ; Muscular Atrophy ; therapy ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; SKP Cullin F-Box Protein Ligases ; metabolism ; Tripartite Motif Proteins ; metabolism ; Ubiquitin-Protein Ligases ; metabolism

BACKGROUNDAmyotrophic lateral sclerosis (ALS) and some mimic disorders, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and spinobulbar muscular atrophy (SBMA) may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders.

METHODSWe compared the abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls.

RESULTSThe ADM/APB CMAP amplitude ratio was significantly higher in the ALS patients (P < 0.001) than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (P < 0.001) and the HD patients (P < 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients (P = 0.004). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P < 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls (P = 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥4.5) were observed exclusively in the ALS patients.

CONCLUSIONSThe different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.

Action Potentials ; Adult ; Aged ; Amyotrophic Lateral Sclerosis ; pathology ; physiopathology ; Diagnosis, Differential ; Female ; Hand ; pathology ; Humans ; Male ; Middle Aged ; Muscle, Skeletal ; physiopathology ; Muscular Atrophy ; pathology ; physiopathology ; Retrospective Studies ; Spinal Muscular Atrophies of Childhood ; pathology ; Spondylosis ; pathology

PURPOSE: Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuron disease characterized by proximal muscle weakness, muscle atrophy, and fasciculation. Although SBMA is not uncommon in Korea, there is only one study reporting clinical characteristics and genotype-phenotype correlation in Korean patients. MATERIALS AND METHODS: In this study, age at the onset of symptoms, the score of severity assessed by impairment of activities of daily living milestones, and rate of disease progression, and their correlations with the number of CAG repeats in the androgen receptor (AR) gene, as well as possible correlations among clinical characteristics, were analyzed in 40 SBMA patients. RESULTS: The median ages at onset and at diagnosis were 44.5 and 52.5 years, respectively, and median interval between onset and diagnosis and median rate of disease progression were 5.0 years and 0.23 score/year, respectively. The median number of CAG repeats in the AR gene was 44 and the number of CAG repeats showed a significant inverse correlation with the age at onset of symptoms (r=-0.407, p=0.009). In addition, patients with early symptom onset had slower rate of disease progression. CONCLUSION: As a report with the largest and recent Korean cohort, this study demonstrates clinical features of Korean patients with SBMA and reaffirms the inverse correlation between the age at disease onset and the number of CAG repeats. Interestingly, this study shows a possibility that the rate of disease progression may be influenced by the age at onset of symptoms.
Activities of Daily Living ; Adult ; Age of Onset ; Asian Continental Ancestry Group/*genetics ; Bulbo-Spinal Atrophy, X-Linked/genetics/*physiopathology ; Disease Progression ; Female ; Genes, Recessive ; Genetic Association Studies ; Genotype ; Humans ; Male ; Middle Aged ; Muscle Weakness/*physiopathology ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic/*genetics ; Phenotype ; Receptors, Androgen/*genetics ; Republic of Korea ; Trinucleotide Repeats/genetics

OBJECTIVESTo compare the paravertebral muscle (such as multifidus, erector spinae, psoas muscle) changes between the patients with degenerative lumbar instability and normal person by MRI and to observe the degeneration of paravertebral muscles. To analyze the relationship between paravertebral muscle degeneration and lumbar curvature of degenerative lumbar instability.

METHODSSixty patients with degenerative lumbar instability were retrospectively enrolled from December 2011 to July 2013 as degeneration group, meanwhile 60 health persons with no degenerative lumbar instability were selected as control group. No significant differences were found in the gender, age and body mass index between the two groups. The cross-sectional area(CSA) and percentage of fat infiltration area (FIA) of the paravertebral muscles at the L4-S1 levels were measured using T2-weighted axial MRI and Image J soft ware. And the lumbar curvature(expressed as lumbar lordosis angle) of all the patients in lumbar X-ray were measured in the two groups. The measured data were analyzed with independent samples t-test.

RESULTSThe difference of multifidus cross-sectional area and the percentage of fat infiltration in the patients of degenerative lumbar instability at the L4-L5, L5-S1 level, compared with the control group, was statistically significant (t = 2.768, t = 6.216, P < 0.05). Between the two groups, the percentage of fatty infiltration in erector spinae showed significant differences (t = 5.862, P < 0.05). The cross-sectional area of erector spinae and the degeneration of the psoas muscle between the two groups was not statistically significant. The lumbar lordsis angle in the patients with degenerative lumbar instability was (43.9 ± 15.6)°, which was higher than the (39.3 ± 14.2)° in control group (t = 2.915, P < 0.05).

CONCLUSIONSCompared with the control group, patients with degenerative lumbar instability exists erector spinae and multifidus muscle degeneration, and erector spinae is more obvious. The degeneration among psoas muscle, erector spinae and multifidus muscle are inconsistent, which may be related to the increasing of the lumbar lordosis angle in the patients with degenerative lumbar instability.

Aged ; Case-Control Studies ; Female ; Humans ; Joint Instability ; diagnosis ; etiology ; pathology ; Lumbosacral Region ; physiopathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscle, Skeletal ; pathology ; Muscular Atrophy ; complications ; diagnosis ; pathology

This study was aimed to investigate the changes of muscle protein synthesis and degradation under different movement conditions, so as to provide theoretical basis for muscle atrophy mechanism. Sprague Dawley (SD) rats were randomly divided into control, endurance training (treadmill training), hind limb overhanging and eccentric training (treadmill training, angle -16º) groups. The gastrocnemius muscles of rats were taken and weighed. The muscle was sectioned, and HE staining was employed to determine the cell's cross-sectional area. Protein expression of p-Akt was measured by immunohistochemistry; and the expressions of MuRF1 and FoxO1 were determined by Western blot. The results showed that, compared with control group, hind limb overhanging and eccentric training groups exhibited decreased muscle weight and cross-sectional area, but endurance training group did not show any changes. The expressions of p-Akt in endurance and eccentric training groups, not in hind limb overhanging group, were significantly higher than that in control group. Compared with that of control, MuRF1 protein remained unchanged in endurance training groups, but was increased in eccentric training and hind limb overhanging groups; FoxO1 protein was decreased in endurance training group, but was increased in eccentric training and hind limb overhanging groups. These results indicate that movement (endurance and eccentric training) can activate Akt expression, but does not increase muscle weight, whereas eccentric training and hind limb overhanging can increase the expressions of MuRF1 and FoxO1, and induce amyotrophy, suggesting MuRF1 and FoxO1 are major determinant factors in muscle atrophy.
Animals ; Forkhead Transcription Factors ; physiology ; Hindlimb Suspension ; Muscle Proteins ; physiology ; Muscle, Skeletal ; physiology ; Muscular Atrophy ; physiopathology ; Nerve Tissue Proteins ; physiology ; Physical Conditioning, Animal ; Proto-Oncogene Proteins c-akt ; physiology ; Rats ; Rats, Sprague-Dawley ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases ; physiology

One of the most important and urgent issues in the field of space medicine is to reveal the potential mechanism underlying the disused muscle atrophy during the weightlessness or microgravity environment. It will conduce to find out effective methods for the prevention and treatment of muscle atrophy during a long-term space flight. Increasing data show that muscle spindle discharges are significantly altered following the hindlimb unloading, suggesting a vital role in the progress of muscle atrophy. In the last decades, we have made a series of studies on changes in the morphological structure and function of muscle spindle following simulated weightlessness. This review will discuss our main results and related researches for understanding of muscle spindle activities during microgravity environment, which may provide a theoretic basis for effective prevention and treatment of muscle atrophy induced by weightlessness.
Animals ; Hindlimb Suspension ; Muscle Spindles ; physiopathology ; Muscle, Skeletal ; physiopathology ; Muscular Atrophy ; physiopathology ; Space Flight ; Weightlessness Simulation

Muscle unloading due to long-term exposure of weightlessness or simulated weightlessness causes atrophy, loss of functional capacity, impaired locomotor coordination, and decreased resistance to fatigue in the antigravity muscles of the lower limbs. Besides reducing astronauts' mobility in space and on returning to a gravity environment, the molecular mechanisms for the adaptation of skeletal muscle to unloading also play an important medical role in conditions such as disuse and paralysis. The tail-suspended rat model was used to simulate the effects of weightlessness on skeletal muscles and to induce muscle unloading in the rat hindlimb. Our series studies have shown that the maximum of twitch tension and the twitch duration decreased significantly in the atrophic soleus muscles, the maximal tension of high-frequency tetanic contraction was significantly reduced in 2-week unloaded soleus muscles, however, the fatigability of high-frequency tetanic contraction increased after one week of unloading. The maximal isometric tension of intermittent tetanic contraction at optimal stimulating frequency did not alter in 1- and 2-week unloaded soleus, but significantly decreased in 4-week unloaded soleus. The 1-week unloaded soleus, but not extensor digitorum longus (EDL), was more susceptible to fatigue during intermittent tetanic contraction than the synchronous controls. The changes in K+ channel characteristics may increase the fatigability during high-frequency tetanic contraction in atrophic soleus muscles. High fatigability of intermittent tetanic contraction may be involved in enhanced activity of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and switching from slow to fast isoform of myosin heavy chain, tropomyosin, troponin I and T subunit in atrophic soleus muscles. Unloaded soleus muscle also showed a decreased protein level of neuronal nitric oxide synthase (nNOS), and the reduction in nNOS-derived NO increased frequency of calcium sparks and elevated intracellular resting Ca2+ concentration ([Ca2+]i) in unloaded soleus muscles. High [Ca2+]i activated calpain-1 which induced a higher degradation of desmin. Desmin degradation may loose connections between adjacent myofibrils and further misaligned Z-disc during repeated tetanic contractions. Passive stretch in unloaded muscle could preserve the stability of sarcoplasmic reticulum Ca2+ release channels by means of keeping nNOS activity, and decrease the enhanced protein level and activity of calpain to control levels in unloaded soleus muscles. Therefore, passive stretch restored normal appearance of Z-disc and resisted in part atrophy of unloaded soleus muscles. The above results indicate that enhanced fatigability of high-frequency tetanic contraction is associated to the alteration in K+ channel characteristics, and elevated SERCA activity and slow to fast transition of myosin heavy chain (MHC) isoforms increases fatigability of intermittent tetanic contraction in atrophic soleus muscle. The sarcomeric damage induced by tetanic contraction can be retarded by stretch in atrophic soleus muscles.
Animals ; Calcium Signaling ; Calpain ; metabolism ; Desmin ; metabolism ; Muscle Contraction ; Muscle Fatigue ; Muscle, Skeletal ; physiopathology ; Muscular Atrophy ; physiopathology ; Myosin Heavy Chains ; metabolism ; Rats ; Sarcoplasmic Reticulum ; pathology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; metabolism ; Weightlessness Simulation

PURPOSE: The purpose of this study was to examine the effects of exercise on muscle weight and Type I and II fiber cross-sectional area of affected and unaffected hindlimb muscles in rats with neuropathic pain induced by unilateral peripheral nerve injury. METHODS: Neuropathic pain was induced by ligation and cutting of the left L5 spinal nerve. Adult male Sprague-Dawley rats were randomly assigned to one of two groups: The Pain+Exercise (PE) group (n=21) and the Sham+Exercise (SE) group (n=20). All rats had 28 sessions of treadmill exercise at grade 10 for 30 minutes, twice/day at 10 m/min for 14 days. Body weight, food intake and activity were measured every day. At 15 days all rats were anesthetized and soleus, plantaris and gastrocnemius muscles were dissected. Muscle weight and Type I, II fiber cross-sectional area of the dissected muscles were measured. RESULTS: The PE group showed significant increases (p<.05), as compared to the SE group for body weight and total diet intake, muscle weight of the unaffected soleus and plantaris, and in Type I and II fiber cross-sectional area of unaffected three muscles and affected plantaris. CONCLUSION: Exercise for 14 days attenuates unaffected soleus, plantaris and gastrocnemius muscle atrophy in neuropathic pain model.
Animals ; Body Weight ; Disease Models, Animal ; Eating ; Hindlimb/*physiology ; Male ; Muscle Fibers, Skeletal/*physiology ; Muscular Atrophy/etiology/physiopathology ; Neuralgia/*etiology ; Peripheral Nerves/*injuries ; *Physical Conditioning, Animal ; Rats ; Rats, Sprague-Dawley

PURPOSE: The purpose of this study was to examine the effects of unilateral sciatic nerve injury on unaffected hindlimb muscles of rats. METHODS: Adult male Sprague-Dawley rats were assigned to one of three groups: control (C) group (n=10) that had no procedures, sham (S) group (n=10) that underwent sham left sciatic nerve transection, and sciatic nerve transection (SNT) group (n=9) that underwent left sciatic nerve transection. At 15 days rats were anesthetized, and the soleus, plantaris and gastrocnemius muscles were dissected. RESULTS: Muscle weight of the unaffected plantaris muscle in the SNT group was significantly lower than in the other two groups. Type II fiber cross-sectional areas of the unaffected plantaris and gastrocnemius muscles in the SNT group were significantly smaller than in the other two groups. The decrease of muscle weights and Type I, II fiber cross-sectional areas of the unaffected three muscles in the SNT group were significantly less than that of the affected three muscles. CONCLUSION: Hindlimb muscle atrophy occurs in the unaffected side after unilateral sciatic nerve injury, with changes in the plantaris and gastrocnemius muscle being more apparent than changes in the soleus muscle. These results have implications for nursing care, in the need to assess degree of muscle atrophy in unaffected muscles as well as affected muscles.
Animals ; Body Weight ; Eating ; Hindlimb ; Male ; Muscle Fibers, Skeletal/*physiology ; Muscle Weakness ; Muscular Atrophy/*etiology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve/*injuries/physiology