RESUMEN
Background: Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia. Methods: Male Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES. Results: In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats. Conclusion: The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.
RESUMEN
Although platelet-rich plasma (PRP) has been widely used regardless of the severity of muscle strain, there have been very few basic studies in which its effects on muscle injury were examined by using models that accurately mimic the clinical muscle strain injury process. Therefore, the aim of this study was to confirm by physiological and structural analyses whether PRP purified by a general preparation method has a muscle healing effect on muscle damage caused by eccentric contraction (ECC). Male Wistar rats were subjected to muscle injury induced by ECC in bilateral plantar flexor muscles using electrical stimulation and an automatically dorsiflexing footplate. The rats were randomly assigned to three groups by type of injection: phosphate-buffered saline (PBS), leukocyte-poor PRP (LP-PRP), or leukocyte-rich PRP (LR-PRP) injection into gastrocnemius muscles three times at weekly intervals. The platelet concentrations of the LP-PRP and LR-PRP were three to five times higher than that of whole blood. The recovery process of torque strength in the plantar flexor muscle, signal changes in MRI images, and histological evaluation 3 weeks after injury showed no obvious differences among the three groups, and every muscle recovered well from the injury without marked fibrosis. The results that neither LP-PRP nor LR-PRP was found to accelerate healing of muscle injuries suggested that conventional preparation and use of PRP for simple muscle injuries caused by muscle strain should be carefully considered, and further basic research using models that accurately mimic clinical practice should be carried out to determine the optimal use of PRP.
Asunto(s)
Músculo Esquelético , Plasma Rico en Plaquetas , Ratas Wistar , Cicatrización de Heridas , Animales , Masculino , Músculo Esquelético/lesiones , Ratas , Imagen por Resonancia Magnética , Esguinces y Distensiones/fisiopatologíaRESUMEN
Chronic kidney disease (CKD)-related cachexia increases the risks of reduced physical activity and mortality. However, the physiological phenotype of skeletal muscle fatigue and changes in intramuscular metabolites during muscle fatigue in CKD-related cachexia remain unclear. In the present study, we performed detailed muscle physiological evaluation, analysis of mitochondrial function, and comprehensive analysis of metabolic changes before and after muscle fatigue in a 5/6 nephrectomized rat model of CKD. Wistar rats were randomized to a sham-operation (Sham) group that served as a control group or a 5/6 nephrectomy (Nx) group. Eight weeks after the operation, in situ torque and force measurements in plantar flexor muscles in Nx rats using electrical stimulation revealed a significant decrease in muscle endurance during subacute phase related to mitochondrial function. Muscle mass was reduced without changes in the proportions of fiber type-specific myosin heavy chain isoforms in Nx rats. Pyruvate-malate-driven state 3 respiration in isolated mitochondria was impaired in Nx rats. Protein expression levels of mitochondrial respiratory chain complexes III and V were decreased in Nx rats. Metabolome analysis revealed that the increased supply of acetyl CoA in response to fatigue was blunted in Nx rats. These findings suggest that CKD deteriorates skeletal muscle endurance in association with mitochondrial dysfunction and inadequate supply of acetyl-CoA during muscle fatigue.NEW & NOTEWORTHY Mitochondrial dysfunction is associated with decreased skeletal muscle endurance in chronic kidney disease (CKD), but the muscle physiological phenotype and major changes in intramuscular metabolites during muscle fatigue in CKD-related cachexia remain unclear. By using a 5/6 nephrectomized CKD rat model, the present study revealed that CKD is associated with reduced tetanic force in response to repetitive stimuli in a subacute phase, impaired mitochondrial respiration, and inadequate supply of acetyl-CoA during muscle fatigue.
Asunto(s)
Fatiga Muscular , Insuficiencia Renal Crónica , Animales , Ratas , Acetilcoenzima A/metabolismo , Caquexia , Músculo Esquelético/metabolismo , Ratas Wistar , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , RespiraciónRESUMEN
Synergist ablation (SA) is an experimental procedure for the induction of hypertrophy. However, SA causes a decrease in specific force (i.e., force per cross-sectional area), likely due to excessive muscle use. Here, we investigated the mechanisms behind the SA-induced intrinsic contractile dysfunction, especially focusing on the excitation-contraction (EC) coupling. Male Wistar rats had unilateral surgical ablation of gastrocnemius and soleus muscles to induce compensatory hypertrophy in the plantaris muscles. Two weeks after SA, plantaris muscle was dissected from each animal and used for later analyses. SA significantly increased the mean fiber cross-sectional area (+18%). On the other hand, the ratio of depolarization-induced force to the maximum Ca2+-activated specific force, an indicator of sarcoplasmic reticulum (SR) Ca2+ release, was markedly reduced in mechanically skinned fibers from the SA group (-51%). These functional defects were accompanied by an extensive fragmentation of the SR Ca2+ release channel, the ryanodine receptor 1 (RyR1), and a decrease in the amount of other triad proteins (i.e., DHPR, STAC3, and junctophilin1). SA treatment also caused activation of calpain-1 and increased the amount of NADPH oxidase 2, endoplasmic reticulum (ER) stress proteins (i.e., Grp78, Grp94, PDI, and Ero1), and lipid peroxidation [i.e., 4-hydroxynonenal (4-HNE)] in SA-treated muscles. Our findings show that SA causes skeletal muscle weakness due to impaired EC coupling. This is likely to be induced by Ca2+-dependent degradation of triad proteins, which may result from Ca2+ leak from fragmented RyR1 triggered by increased oxidative stress.NEW & NOTEWORTHY Synergist ablation (SA) has widely been used to understand the mechanisms behind skeletal muscle hypertrophy. However, compensatory hypertrophied muscles display intrinsic contractile dysfunction, i.e., a hallmark of overuse. Here, we demonstrate that SA-induced compensatory hypertrophy is accompanied by muscle weakness due to impaired sarcoplasmic reticulum Ca2+ release. This dysfunction may be caused by the degradation of triad proteins due to the reciprocal amplification of reactive oxygen species and Ca2+ signaling at the junctional space microdomain.
Asunto(s)
Canal Liberador de Calcio Receptor de Rianodina , Retículo Sarcoplasmático , Ratas , Animales , Masculino , Retículo Sarcoplasmático/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Ratas Wistar , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Debilidad Muscular/metabolismo , Hipertrofia/metabolismo , Calcio/metabolismoRESUMEN
Duchenne muscular dystrophy is a genetic muscle-wasting disorder characterized by progressive muscle weakness and easy fatigability. Here we examined whether high-intensity interval training (HIIT) in the form of isometric contraction improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice. Isometric HIIT was performed on plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 weeks (a total of 15 sessions). In the non-trained contralateral gastrocnemius muscle from mdx52 mice, the decreased fatigue resistance was associated with a reduction in the amount of peroxisome proliferator-activated receptor γ coactivator 1-α, citrate synthase activity, mitochondrial respiratory complex II, LC3B-II/I ratio, and mitophagy-related gene expression (i.e. Pink1, parkin, Bnip3 and Bcl2l13) as well as an increase in the phosphorylation levels of Src Tyr416 and Akt Ser473, the amount of p62, and the percentage of Evans Blue dye-positive area. Isometric HIIT restored all these alterations and markedly improved fatigue resistance in mdx52 muscles. Moreover, an acute bout of HIIT increased the phosphorylation levels of AMP-activated protein kinase (AMPK) Thr172, acetyl CoA carboxylase Ser79, unc-51-like autophagy activating kinase 1 (Ulk1) Ser555, and dynamin-related protein 1 (Drp1) Ser616 in mdx52 muscles. Thus, our data show that HIIT with isometric contractions significantly mitigates histological signs of pathology and improves fatigue resistance in dystrophin-deficient muscles. These beneficial effects can be explained by the restoration of mitochondrial function via AMPK-dependent induction of the mitophagy programme and de novo mitochondrial biogenesis. KEY POINTS: Skeletal muscle fatigue is often associated with Duchenne muscular dystrophy (DMD) and leads to an inability to perform daily tasks, profoundly decreasing quality of life. We examined the effect of high-intensity interval training (HIIT) in the form of isometric contraction on fatigue resistance in skeletal muscle from the mdx52 mouse model of DMD. Isometric HIIT counteracted the reduced fatigue resistance as well as dystrophic changes in skeletal muscle of mdx52 mice. This beneficial effect could be explained by the restoration of mitochondrial function via AMP-activated protein kinase-dependent mitochondrial biogenesis and the induction of the mitophagy programme in the dystrophic muscles.
Asunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Distrofia Muscular de Duchenne , Ratones , Animales , Distrofina/genética , Distrofina/metabolismo , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/genética , Contracción Isométrica , Proteínas Quinasas Activadas por AMP/metabolismo , Calidad de Vida , Ratones Endogámicos mdx , Músculo Esquelético/fisiología , Contracción Muscular/fisiologíaRESUMEN
A 67-year-old man was admitted to our hospital with a high fever. Laboratory tests revealed leukopenia, thrombocytopenia, liver dysfunction, rhabdomyolysis, and hyperferritinemia. He was diagnosed with severe fever with thrombocytopenia syndrome (SFTS) complicated by hemophagocytic lymphohistiocytosis and treated with steroid therapy, intravenous calcium channel blocker (CCB), and supportive care, without favipiravir. Serum levels of ferritin and soluble interleukin 2 receptor (sIL2R) were markedly elevated on Day 3 after admission and decreased thereafter, while an SFTS viral load of 6.8×104 copies/µL was detected on Day 2, increasing to 2.9×105 copies/µL on Day 6. Serum ferritin and sIL2R levels may be better indicators of mortality than the SFTS viral load, and CCBs may have a therapeutic effect.
Asunto(s)
Linfohistiocitosis Hemofagocítica , Phlebovirus , Síndrome de Trombocitopenia Febril Grave , Trombocitopenia , Masculino , Humanos , Anciano , Síndrome de Trombocitopenia Febril Grave/complicaciones , Bloqueadores de los Canales de Calcio/uso terapéutico , Nicardipino , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/diagnóstico , Trombocitopenia/complicaciones , Trombocitopenia/tratamiento farmacológico , FerritinasRESUMEN
In the present study, we examined neural circuit formation in the forebrain of the Olig2 knockout (Olig2-KO) mouse model and found disruption of the anterior commissure at the late foetal stage. Axon bundles of the anterior commissure encountered the wall of the third ventricle and ceased axonal extension. L1-CAM immunohistochemistry showed that Olig2-KO mice lose decussation formation in the basal forebrain. DiI tracing revealed that the thin bundles of the anterior commissure axons crossed the midline but ceased further extension into the deep part of the contralateral side. Furthermore, some fractions of DiI-labelled axons were oriented dorsolaterally, which was not observed in the control mouse forebrain. The rostral part of the third ventricle was much wider in the Olig2-KO mice than in wild-type mice, which likely resulted in the delay of midline fusion and subsequent delay and malformation of the anterior commissure. We analysed gene expression alterations in the Olig2-KO mice using a public database and found multiple genes, which are related to axon guidance and epithelial-mesenchymal transition, showing subtle expression changes. These results suggest that Olig2 is essential for anterior commissure formation, likely by regulating multiple biological processes.
Asunto(s)
Axones , Prosencéfalo , Animales , Ratones , Prosencéfalo/metabolismo , Axones/fisiología , Ratones Noqueados , Factor de Transcripción 2 de los Oligodendrocitos/genética , Factor de Transcripción 2 de los Oligodendrocitos/metabolismoRESUMEN
The disruption of excitation-contraction (EC) coupling and subsequent reduction in Ca2+ release from the sarcoplasmic reticulum (SR) have been shown to account for muscle weakness seen in patients with Duchenne muscular dystrophy (DMD). Here, we examined the mechanisms underlying EC uncoupling in skeletal muscles from mdx52 and DMD-null/NSG mice, animal models for DMD, focusing on the SH3 and cysteine-rich domain 3 (STAC3) and junctophilin 1 (JP1), which link the dihydropyridine receptor (DHPR) in the transverse tubule and the ryanodine receptor 1 in the SR. The isometric plantarflexion torque normalized to muscle weight of whole plantar flexor muscles was depressed in mdx52 and DMD-null/NSG mice compared with their control mice. This was accompanied by increased autolysis of calpain-1, decreased levels of STAC3 and JP1 content, and dissociation of STAC3 and JP1 from DHPR-α1s in gastrocnemius muscles. Moreover, in vitro mechanistic experiments demonstrated that STAC3 and JP1 underwent Ca2+-dependent proteolysis that was less pronounced in dystrophin-deficient muscles where calpastatin, the endogenous calpain inhibitor, was upregulated. Eccentric contractions further enhanced autolysis of calpain-1 and proteolysis of STAC3 and JP1 that were associated with severe torque depression in gastrocnemius muscles from DMD-null/NSG mice. These data suggest that Ca2+-dependent proteolysis of STAC3 and JP1 may be an essential factor causing muscle weakness due to EC coupling failure in dystrophin-deficient muscles.NEW & NOTEWORTHY The mechanisms underlying the disruption of excitation-contraction (EC) coupling in dystrophin-deficient muscles are not well understood. Here, using animal models for Duchenne muscular dystrophies (DMD), we show a Ca2+-dependent protease (calpain-1)-mediated proteolysis of SH3 and cysteine-rich domain 3 (STAC3) and junctophilin 1 (JP1), essential EC coupling proteins, in dystrophin-deficient muscle, and highlighting the dissociation of STAC3 and JP1 from dihydropyridine receptor as a causative factor in EC uncoupling of dystrophic muscles.
Asunto(s)
Canales de Calcio Tipo L , Distrofia Muscular de Duchenne , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/metabolismo , Calpaína/metabolismo , Cisteína/metabolismo , Distrofina/genética , Distrofina/metabolismo , Proteínas de la Membrana , Ratones , Ratones Endogámicos mdx , Debilidad Muscular/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismoRESUMEN
BACKGROUND: Muscle weakness and decreased fatigue resistance are key manifestations of systemic autoimmune myopathies (SAMs). We here examined whether high-intensity interval training (HIIT) improves fatigue resistance in the skeletal muscle of experimental autoimmune myositis (EAM) mice, a widely used animal model for SAM. METHODS: Female BALB/c mice were randomly assigned to control (CNT) or EAM groups (n = 28 in each group). EAM was induced by immunization with three injections of myosin emulsified in complete Freund's adjuvant. The plantar flexor (PF) muscles of mice with EAM were exposed to either an acute bout or 4 weeks of HIIT (a total of 14 sessions). RESULTS: The fatigue resistance of PF muscles was lower in the EAM than in the CNT group (P < 0.05). These changes were associated with decreased activities of citrate synthase and cytochrome c oxidase and increased expression levels of the endoplasmic reticulum stress proteins (glucose-regulated protein 78 and 94, and PKR-like ER kinase) (P < 0.05). HIIT restored all these alterations and increased the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the mitochondrial electron transport chain complexes (I, III, and IV) in the muscles of EAM mice (P < 0.05). CONCLUSIONS: HIIT improves fatigue resistance in a SAM mouse model, and this can be explained by the restoration of mitochondria oxidative capacity via inhibition of the ER stress pathway and PGC-1α-mediated mitochondrial biogenesis.
Asunto(s)
Entrenamiento de Intervalos de Alta Intensidad , Enfermedad Autoinmune Experimental del Sistema Nervioso , Animales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Mitocondrias , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Enfermedad Autoinmune Experimental del Sistema Nervioso/metabolismo , Enfermedad Autoinmune Experimental del Sistema Nervioso/terapiaRESUMEN
A 45-year-old Japanese man presenting with leg purpura, abdominal pain, and arthralgia was diagnosed with IgA vasculitis. His symptoms resolved after the intravenous administration of prednisolone. However, on day 20 of admission, he experienced bloody discharge and hypovolemic shock. The bleeding point was not identified on contrast-enhanced computed tomography scanning. The blood loss was approximately 10800ml and the patient received transfusions of 48 units of concentrated red blood cells, 18 units of fresh frozen plasma, and 30 units of concentrated platelets. Laparotomy and enteroscopy were performed through the incision of the jejunum to detect the bleeding source. Spurting bleeding was observed during the enteroscopy and partial resection of the jejunum was performed. Histopathological examination of the resected specimen revealed large vessels beneath the jejunal ulcer scar, suggesting bleeding from a Dieulafoy's lesion. Leukocytoclastic vasculitis or cytomegalovirus infection was not observed in the resected specimen. Gastrointestinal symptoms in patients with IgA vasculitis usually improve with bowel rest and conservative treatment. Administration of steroids or factor XIII is recommended for patients with severe abdominal pain refractory to conservative management. Rarely, massive bleeding, perforation, intussusception, and/or intestinal obstruction occur in the gastrointestinal tract and these complications affect patients' prognoses. The clinical course in the present patient indicated that severe bleeding from the gastrointestinal tract can occur even after symptom remission in patients with IgA vasculitis. In such cases, prompt treatment, including laparotomy and/or enteroscopy, is essential.
Asunto(s)
Inmunoglobulina A/metabolismo , Yeyuno , Vasculitis/diagnóstico , Antiinflamatorios/uso terapéutico , Hemorragia Gastrointestinal , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Vasculitis Leucocitoclástica CutáneaRESUMEN
A 64-year-old Japanese man suffered cardiopulmonary arrest, which may have resulted from sepsis and/or hyperosmolar hyperglycemic non-ketonic coma, and was admitted after successful resuscitation. He had watery diarrhea on day 18 and was diagnosed with cytomegalovirus enterocolitis. In addition, computed tomography performed on day 27 and colonoscopy revealed gastric emphysema and intestinal pseudolipomatosis, respectively. This report is the first to describe a patient with cytomegalovirus enterocolitis and subsequent gastric emphysema and pseudolipomatosis. Gastrointestinal cytomegalovirus infection may underlie gastric emphysema and intestinal pseudolipomatosis, particularly in patients with relative or obvious immune dysfunction.