Skeletal muscle dysfunction is a common extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with decreased quality-of-life and survival in patients. The autophagy lysosome pathway is one of the proteolytic systems that significantly affect skeletal muscle structure and function. Intriguingly, both promoting and inhibiting autophagy have been observed to improve COPD skeletal muscle dysfunction, yet the mechanism is unclear. This paper first reviewed the effects of macroautophagy and mitophagy on the structure and function of skeletal muscle in COPD, and then explored the mechanism of autophagy mediating the dysfunction of skeletal muscle in COPD. The results showed that macroautophagy- and mitophagy-related proteins were significantly increased in COPD skeletal muscle. Promoting macroautophagy in COPD improves myogenesis and replication capacity of muscle satellite cells, while inhibiting macroautophagy in COPD myotubes increases their diameters. Mitophagy helps to maintain mitochondrial homeostasis by removing impaired mitochondria in COPD. Autophagy is a promising target for improving COPD skeletal muscle dysfunction, and further research should be conducted to elucidate the specific mechanisms by which autophagy mediates COPD skeletal muscle dysfunction, with the aim of enhancing our understanding in this field.
Pulmonary Disease, Chronic Obstructive/physiopathology* ; Autophagy/physiology* ; Humans ; Muscle, Skeletal/pathology* ; Mitophagy ; Animals ; Mitochondria/metabolism* ; Lysosomes

The maintenance of skeletal muscle quality involves various signal pathways that interact with each other. Under normal physiological conditions, these intersecting signal pathways regulate and coordinate the hypertrophy and atrophy of skeletal muscles, balancing the protein synthesis and degradation of muscle. When the total rate of protein synthesis exceeds that of protein degradation, the muscle gradually becomes enlarged, while when the total rate of protein synthesis is lower than that of protein degradation, the muscle shrinks. Myocyte atrophy mainly involves two protein degradation pathways, namely ubiquitin-proteasome and autophagy-lysosome. Protein degradation pathway is activated during muscle atrophy, resulting in the loss of muscle mass. Muscle atrophy can occur under various conditions such as malnutrition, aging and cachexia. Skeletal muscle atrophy caused by orthopedic diseases mainly includes disuse muscular atrophy caused by fracture and denervation muscular atrophy. The signal pathways that control and coordinate protein synthesis and degradation in skeletal muscle include insulin-like growth factor 1 (IGF1)-Akt-mammalian target of rapamycin (mTOR), myostatin-activin A-Smad, G protein α inhibitory peptide 2 (Gαi2)-PKC, nuclear factor κB (NF-κB), ectodysplasin A2 receptor (EDA2R)-NF-κB inducing kinase (NIK) and mitogen-activated protein kinase (MAPK) pathways. This paper provides a comprehensive review of the protein degradation pathways in skeletal muscle atrophy and the associated signal pathways regulating protein degradation in muscular atrophy.
Humans ; Muscular Atrophy/etiology* ; Muscle, Skeletal/pathology* ; Signal Transduction ; Animals ; Insulin-Like Growth Factor I/metabolism* ; Myostatin/physiology* ; TOR Serine-Threonine Kinases/metabolism* ; Autophagy/physiology* ; NF-kappa B/metabolism* ; Proteolysis ; Proteasome Endopeptidase Complex/physiology*

BACKGROUND: Late-onset multiple acyl-coA dehydrogenase deficiency (MADD) is an autosomal recessive inherited metabolic disorder. It is still unclear about the muscle magnetic resonance image (MRI) pattern of the distal lower limb pre- and post-treatment in patients with late-onset MADD. This study described the clinical and genetic findings in a cohort of patients with late-onset MADD, and aimed to characterize the MRI pattern of the lower limbs. METHODS: Clinical data were retrospectively collected from clinic centers of Peking University People's Hospital between February 2014 and February 2018. Muscle biopsy, blood acylcarnitines, and urine organic acids profiles, and genetic analysis were conducted to establish the diagnosis of MADD in 25 patients. Muscle MRI of the thigh and leg were performed in all patients before treatment. Eight patients received MRI re-examinations after treatment. RESULTS: All patients presented with muscle weakness or exercise intolerance associated with variants in the electron transfer flavoprotein dehydrogenase gene. Muscle MRI showed a sign of both edema-like change and fat infiltration selectively involving in the soleus (SO) but sparing of the gastrocnemius (GA) in the leg. Similar sign of selective involvement of the biceps femoris longus (BFL) but sparing of the semitendinosus (ST) was observed in the thigh. The sensitivity and specificity of the combination of either "SO+/GA-" sign or "BFL+/ST-" sign for the diagnosis of late-onset MADD were 80.0% and 83.5%, respectively. Logistic regression model supported the findings. The edema-like change in the SO and BFL muscles were quickly recovered at 1 month after treatment, and the clinical symptom was also relieved. CONCLUSIONS This study expands the clinical and genetic spectrums of late-onset MADD. Muscle MRI shows a distinct pattern in the lower limb of patients with late-onset MADD. The dynamic change of edema-like change in the affected muscles might be a potential biomarker of treatment response.
Adolescent ; Adult ; Biopsy ; methods ; Carnitine ; analogs & derivatives ; blood ; Electron-Transferring Flavoproteins ; genetics ; Female ; Hamstring Muscles ; diagnostic imaging ; metabolism ; pathology ; Humans ; Iron-Sulfur Proteins ; genetics ; Magnetic Resonance Imaging ; methods ; Male ; Middle Aged ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; diagnostic imaging ; genetics ; pathology ; Muscle, Skeletal ; diagnostic imaging ; metabolism ; pathology ; Oxidoreductases Acting on CH-NH Group Donors ; genetics ; Retrospective Studies ; Young Adult

The clinical treatment of joint contracture due to immobilization remains difficult. The pathological changes of muscle tissue caused by immobilization-induced joint contracture include disuse skeletal muscle atrophy and skeletal muscle tissue fibrosis. The proteolytic pathways involved in disuse muscle atrophy include the ubiquitin-proteasome-dependent pathway, caspase system pathway, matrix metalloproteinase pathway, Ca-dependent pathway and autophagy-lysosomal pathway. The important biological processes involved in skeletal muscle fibrosis include intermuscular connective tissue thickening caused by transforming growth factor-β1 and an anaerobic environment within the skeletal muscle leading to the induction of hypoxia-inducible factor-1α. This article reviews the progress made in understanding the pathological processes involved in immobilization-induced muscle contracture and the currently available treatments. Understanding the mechanisms involved in immobilization-induced contracture of muscle tissue should facilitate the development of more effective treatment measures for the different mechanisms in the future.
Atrophy ; Autophagy ; Calcium ; metabolism ; Caspases ; metabolism ; Connective Tissue ; metabolism ; pathology ; Contracture ; etiology ; metabolism ; pathology ; therapy ; Fibrosis ; Humans ; Immobilization ; adverse effects ; Joints ; Lysosomes ; metabolism ; Matrix Metalloproteinases ; metabolism ; Muscle, Skeletal ; metabolism ; pathology ; Proteasome Endopeptidase Complex ; metabolism ; Proteolysis ; Signal Transduction ; physiology ; Transforming Growth Factor beta1 ; metabolism ; Ubiquitin ; metabolism

Objective To investigate the expression of cannabinoid type 2 receptor （CB2R） at different time points after brain contusion and its relationship with wound age of mice. Methods A mouse brain contusion model was established with PCI3000 Precision Cortical Impactor. Expression changes of CB2R around the injured area were detected with immunohistochemical staining, immunofluorescent staining and Western blotting at different time points. Results Immunohistochemical staining results showed that only a few cells in the cerebral cortex of the sham operated group had CB2R positive expression. The ratio of CB2R positive cells gradually increased after injury and reached the peak twice at 12 h and 7 d post-injury, followed by a decrease to the normal level 28 d post-injury. The results of Western blotting were consistent with the immunohistochemical staining results. Immunofluorescent staining demonstrated that the changes of the ratio of CB2R positive cells in neurons, CB2R positive cells in monocytes and CB2R positive cells in astrocytes to the total cell number showed a single peak pattern, which peaked at 12 h, 1 d and 7 d post-injury, respectively. Conclusion The expression of CB2R after brain contusion in neurons, monocytes and astrocytes in mice suggests that it is likely to be involved in the regulation of the biological functions of those cells. The changes in CB2R are time-dependent, which suggests its potential applicability as a biological indicator for wound age estimation of brain contusion in forensic practice.
Animals ; Blotting, Western ; Brain Contusion/metabolism* ; Brain Injuries ; Forensic Pathology ; Mice ; Muscle, Skeletal/pathology* ; Receptor, Cannabinoid, CB2/metabolism* ; Receptors, Cannabinoid ; Time Factors ; Wound Healing/physiology*

Objective To explore the application of neutrophil migration distance for wound age estimation of skeletal muscles in rats, and to provide methodological basis for follow-up study in future. Methods The skeletal muscle contusion model was established in rats, and the control group and the 2, 4, 6 h post-traumatic groups were set. The law of response of neutrophils that participated in the inflammation after injury was detected by immunohistochemical staining, and the relationship between neutrophil migration distance and injury time was detected by TissueFAXS PLUS software. Results The skeletal muscle was obviously infiltrated with neutrophils 2-6 h after injury. The positive rate of neutrophil was （28.75±0.94）% at 2 h post-traumatic, and reached the peak （45.50±3.63）% at 4 h post-traumatic, then decreased to （31.92±1.56）% at 6 h post-traumatic. The neutrophil migration distances increased with the progress of inflammation, and reached （124.80±12.32） μm, （229.03±21.45） μm and （335.04±16.75） μm at 2 h, 4 h and 6 h, respectively. Conclusion There is a relationship of neutrophil infiltrated number and migration distance and wound age within the 2-6 h after skeletal muscle injury, which could be used for the inference of skeletal muscle wound age.
Animals ; Contusions/metabolism* ; Follow-Up Studies ; Muscle, Skeletal/pathology* ; Neutrophil Infiltration ; Neutrophils ; Rats ; Rats, Sprague-Dawley ; Time Factors

Active Transport, Cell Nucleus ; Animals ; Cell Nucleus ; metabolism ; Forkhead Box Protein O3 ; metabolism ; Mice ; Mice, Knockout ; Muscle, Skeletal ; metabolism ; pathology ; Muscular Atrophy ; metabolism ; pathology ; Protein-Serine-Threonine Kinases ; deficiency ; metabolism

OBJECTIVES: To investigate the time-dependent expression of metallothionein （MT） 1A mRNA and MT2A mRNA in contused skeletal muscle of rats. METHODS: A total of 54 Sprague-Dawley rats were used in this study. The rats were divided into two parts: control group （n=6） and contusion groups （0.5, 1, 6, 12, 18, 24, 30, and 36 h after contusion, n=6）. Total RNA was extracted from skeletal muscle. The expression levels of MT1A mRNA and MT2A mRNA were detected by SYBR Green I real-time PCR. RESULTS: The expression trends of the two potential marker genes were related to wound age. In addition to 0.5 h, there were significant contrasts between the control group and contused group （P<0.05）, about the expression levels of MT1A mRNA and MT2A mRNA in different phases. As the extension of wound age, the relative expression of MT1A mRNA and MT2A mRNA at 1 h, 6 h, 12 h and 18 h after contusion demonstrated upgrade tendency until its expression levels in 18 h peak with 239.41±15.20 and 717.42±50.76, respectively. When time extends to 24 h after injury, the expression of above two marks decreased, respectively. The MT1A mRNA and MT2A mRNA expression levels increased at 30 h and then decreased. CONCLUSIONS Determination of MT1A mRNA and MT2A mRNA levels by real-time PCR may be useful for the estimation of wound age.
Animals ; Contusions/pathology* ; Gene Expression Regulation ; Genetic Markers ; Metallothionein ; Muscle, Skeletal/metabolism* ; RNA, Messenger/metabolism* ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Time Factors ; Wound Healing

BACKGROUNDLipid storage myopathy (LSM) is a genetically heterogeneous group with variable clinical phenotypes. Late-onset multiple acyl-coenzyme A dehydrogenation deficiency (MADD) is a rather common form of LSM in China. Diagnosis and clinical management of it remain challenging, especially without robust muscle biopsy result and genetic detection. As the noninvasion and convenience, muscle magnetic resonance imaging (MRI) is a helpful assistant, diagnostic tool for neuromuscular disorders. However, the disease-specific MRI patterns of muscle involved and its diagnostic value in late-onset MADD have not been systematic analyzed.

METHODSWe assessed the MRI pattern and fat infiltration degree of the lower limb muscles in 28 late-onset MADD patients, combined with detailed clinical features and gene spectrum. Fat infiltration degree of the thigh muscle was scored while that of gluteus was described as obvious or not. Associated muscular atrophy was defined as obvious muscle bulk reduction.

RESULTSThe mean scores were significantly different among the anterior, medial, and posterior thigh muscle groups. The mean of fat infiltration scores on posterior thigh muscle group was significantly higher than either anterior or medial thigh muscle group (P < 0.001). Moreover, the mean score on medial thigh muscle group was significantly higher than that of anterior thigh muscle group (P < 0.01). About half of the patients displayed fat infiltration and atrophy in gluteus muscles. Of 28 patients, 12 exhibited atrophy in medial and/or posterior thigh muscle groups, especially in posterior thigh muscle group. Muscle edema pattern was not found in all the patients.

CONCLUSIONSLate-onset MADD patients show a typical muscular imaging pattern of fat infiltration and atrophy on anterior, posterior, and medial thigh muscle groups, with major involvement of posterior thigh muscle group and gluteus muscles and a sparing involvement of anterior thigh compartment. Our findings also suggest that muscle MRI of lower limbs is a helpful tool in guiding clinical evaluation on late-onset MADD.

Adolescent ; Adult ; Age of Onset ; Child ; Child, Preschool ; Electron-Transferring Flavoproteins ; genetics ; Female ; Humans ; Lipid Metabolism, Inborn Errors ; genetics ; metabolism ; pathology ; Lower Extremity ; pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Muscle, Skeletal ; metabolism ; pathology ; Muscular Atrophy ; genetics ; metabolism ; pathology ; Muscular Dystrophies ; genetics ; metabolism ; pathology ; Mutation ; genetics ; Young Adult

BACKGROUNDCollagen VI-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Muscle magnetic resonance imaging (MRI) has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies.

METHODSEleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders (disease controls). T1-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri's scale. We assessed the sensitivity and specificity of the MRI features of collagen VI-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated.

RESULTSEleven patients with collagen VI gene mutation-related myopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius (P = 0.033); therefore, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A "target" sign in rectus femoris (RF) was present in seven cases, and a "sandwich" sign in vastus lateralis (VL) was present in ten cases. The "target" and "sandwich" signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes.

CONCLUSIONSThe "target" sign in RF and "sandwich" sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.

Adolescent ; Adult ; Child ; Child, Preschool ; Collagen Type VI ; genetics ; metabolism ; Female ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Male ; Muscle, Skeletal ; pathology ; Muscular Diseases ; genetics ; metabolism ; pathology ; Mutation ; genetics ; Sensitivity and Specificity ; Thigh ; pathology ; Young Adult