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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445538

RESUMO

Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing inflammation. Whether decellularized biomaterials derived from aged muscle would suffer from increased AGE collagen cross-links is unknown. We characterized gastrocnemii of 1-, 2-, and 20-month-old C57BL/6J mice before and after decellularization to determine age-dependent changes to collagen stiffness and AGE cross-linking. Total and soluble collagen was measured to assess if age-dependent increases in collagen and cross-linking persisted in decellularized muscle matrix (DMM). Stiffness of aged DMM was determined using atomic force microscopy. AGE levels and the effect of an AGE cross-link breaker, ALT-711, were tested in DMM samples. Our results show that age-dependent increases in collagen amount, cross-linking, and general stiffness were observed in DMM. Notably, we measured increased AGE-specific cross-links within old muscle, and observed that old DMM retained AGE cross-links using ALT-711 to reduce AGE levels. In conclusion, deleterious age-dependent modifications to collagen are present in DMM from old muscle, implying that age matters when sourcing skeletal muscle extracellular matrix as a biomaterial.


Assuntos
Envelhecimento/metabolismo , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Músculo Esquelético/metabolismo , Envelhecimento/patologia , Animais , Matriz Extracelular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia
2.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445567

RESUMO

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Fibrose/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Mioblastos/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Fibrose/metabolismo , Fibrose/patologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Receptores de Lisoesfingolipídeo
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445295

RESUMO

Skeletal muscle is affected in experimental autoimmune encephalomyelitis (EAE), which is a model of multiple sclerosis that produces changes including muscle atrophy; histological features of neurogenic involvement, and increased oxidative stress. In this study, we aimed to evaluate the therapeutic effects of transcranial magnetic stimulation (TMS) on the involvement of rat skeletal muscle and to compare them with those produced by natalizumab (NTZ). EAE was induced by injecting myelin oligodendrocyte glycoprotein (MOG) into Dark Agouti rats. Both treatments, NTZ and TMS, were implemented from day 15 to day 35. Clinical severity was studied, and after sacrifice, the soleus and extensor digitorum longus muscles were extracted for subsequent histological and biochemical analysis. The treatment with TMS and NTZ had a beneficial effect on muscle involvement in the EAE model. There was a clinical improvement in functional motor deficits, atrophy was attenuated, neurogenic muscle lesions were reduced, and the level of oxidative stress biomarkers was lower in both treatment groups. Compared to NTZ, the best response was obtained with TMS for all the parameters analyzed. The myoprotective effect of TMS was higher than that of NTZ. Thus, the use of TMS may be an effective strategy to reduce muscle involvement in multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/terapia , Atrofia Muscular/prevenção & controle , Estimulação Magnética Transcraniana , Animais , Contagem de Células , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Glicoproteína Mielina-Oligodendrócito , Natalizumab/farmacologia , Ratos
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360831

RESUMO

The neuromuscular junction (NMJ) is a specialized synapse that bridges the motor neuron and the skeletal muscle fiber and is crucial for conversion of electrical impulses originating in the motor neuron to action potentials in the muscle fiber. The consideration of contributing factors to skeletal muscle injury, muscular dystrophy and sarcopenia cannot be restricted only to processes intrinsic to the muscle, as data show that these conditions incur denervation-like findings, such as fragmented NMJ morphology and corresponding functional changes in neuromuscular transmission. Primary defects in the NMJ also influence functional loss in motor neuron disease, congenital myasthenic syndromes and myasthenia gravis, resulting in skeletal muscle weakness and heightened fatigue. Such findings underscore the role that the NMJ plays in neuromuscular performance. Regardless of cause or effect, functional denervation is now an accepted consequence of sarcopenia and muscle disease. In this short review, we provide an overview of the pathologic etiology, symptoms, and therapeutic strategies related to the NMJ. In particular, we examine the role of the NMJ as a disease modifier and a potential therapeutic target in neuromuscular injury and disease.


Assuntos
Envelhecimento/patologia , Músculo Esquelético/patologia , Doenças Neuromusculares/patologia , Junção Neuromuscular/patologia , Animais , Humanos
5.
FASEB J ; 35(9): e21860, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34411340

RESUMO

Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we stimulated the sciatic nerve of wild-type littermates (WT) (n = 6) and animals carrying the mutation (MUT) (n = 6) causing a lengthening contraction of the dorsi flexor muscles. MUT animals showed signs of ongoing regeneration at baseline as indicated by a higher number of central nuclei (genotype: P < .0001). While stimulation did not impact central nuclei, we found an increased number of IgG positive fibers (membrane damage indicator) after eccentric contractions with both genotypes (stimulation: P < .01). Interestingly, WT animals displayed a more pronounced increase in IgG positive fibers with stimulation compared to MUT (interaction: P < .05). In addition to altered histology, molecular signaling on the protein level differed between WT and MUT. The membrane repair protein dysferlin decreased with eccentric loading in WT but increased in MUT (interaction: P < .05). The autophagic substrate p62 was increased in both genotypes with loading (stimulation: P < .05) but tended to be more elevated in WT (interaction: P = .05). Caspase 3 levels, a central regulator of apoptotic cell death, was increased with stimulation in both genotypes (stimulation: P < .01) but more so in WT animals (interaction: P < .0001). Overall, our data indicate that R349P Des rats have a lower susceptibility to structural muscle damage of the cytoskeleton and sarcolemma with acute eccentric loading.


Assuntos
Desmina/genética , Contração Muscular , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Mutação , Doença Aguda , Animais , Apoptose , Doença Crônica , Colágeno/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , Feminino , Masculino , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Ratos , Risco
6.
FASEB J ; 35(9): e21861, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416029

RESUMO

Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium-chain triglycerides (MCT-KD) could alter genetically mutated DMD in model rats. We found that the MCT-KD significantly increased muscle strength and fiber diameter in these rats. The MCT-KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT-KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT-KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT-KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT-KD-induced improvement of DMD.


Assuntos
Dieta Cetogênica , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Distrofia Muscular de Duchenne/dietoterapia , Distrofia Muscular de Duchenne/fisiopatologia , Triglicerídeos/química , Triglicerídeos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/dietoterapia , Fibrose/patologia , Inflamação/dietoterapia , Inflamação/patologia , Cetonas/sangue , Cetose , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Necrose/dietoterapia , Necrose/patologia , Ratos , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Triglicerídeos/uso terapêutico
7.
FASEB J ; 35(9): e21862, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416035

RESUMO

Loss of muscle mass and strength after disuse followed by impaired muscle recovery commonly occurs with aging. Metformin (MET) and leucine (LEU) individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor tested as a remedy to enhance muscle recovery following disuse atrophy in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET + LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice and if these muscle responses correspond to changes in satellite cells and collagen remodeling. Aged mice (22-24 months) underwent 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14 days RL). MET, LEU, or MET + LEU was administered via drinking water and were compared to Vehicle (standard drinking water) and ambulatory baseline. We observed that during HU, MET + LEU resolved whole body grip strength and soleus muscle specific force decrements caused by HU. Gastrocnemius satellite cell abundance was increased with MET + LEU treatment but did not alter muscle size during disuse or recovery conditions. Moreover, MET + LEU treatment alleviated gastrocnemius collagen accumulation caused by HU and increased collagen turnover during 7 and 14 days RL driven by a decrease in collagen IV content. Transcriptional pathway analysis revealed that MET + LEU altered muscle hallmark pathways related to inflammation and myogenesis during HU. Together, the dual treatment of MET and LEU was able to increase muscle function, satellite cell content, and reduce collagen accumulation, thus improving muscle quality during disuse and recovery in aging.


Assuntos
Envelhecimento , Colágeno/metabolismo , Leucina/uso terapêutico , Metformina/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Elevação dos Membros Posteriores , Imunoglobulina G/análise , Leucina/farmacologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Tamanho do Órgão/efeitos dos fármacos , RNA-Seq , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais/efeitos dos fármacos
8.
FASEB J ; 35(9): e21819, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34405910

RESUMO

Skeletal muscle contains multiple cell types that work together to maintain tissue homeostasis. Among these, satellite cells (SC) and fibroadipogenic progenitors cells (FAPs) are the two main stem cell pools. Studies of these cells using animal models have shown the importance of interactions between these cells in repair of healthy muscle, and degeneration of dystrophic muscle. Due to the unavailability of fresh patient muscle biopsies, similar analysis of interactions between human FAPs and SCs is limited especially among the muscular dystrophy patients. To address this issue here we describe a method that allows the use of frozen human skeletal muscle biopsies to simultaneously isolate and grow SCs and FAPs from healthy or dystrophic patients. We show that while the purified SCs differentiate into mature myotubes, purified FAPs can differentiate into adipocytes or fibroblasts demonstrating their multipotency. We find that these FAPs can be immortalized and the immortalized FAPs (iFAPs) retain their multipotency. These approaches open the door for carrying out personalized analysis of patient FAPs and interactions with the SCs that lead to muscle loss.


Assuntos
Biópsia , Separação Celular , Criopreservação , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/patologia , Distrofia Muscular de Duchenne/patologia , Adulto Jovem
9.
Sci Transl Med ; 13(605)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349036

RESUMO

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.


Assuntos
Caquexia , Neoplasias , Animais , Denervação , Humanos , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular , Neoplasias/complicações , Neoplasias/patologia
10.
BMC Musculoskelet Disord ; 22(1): 680, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380439

RESUMO

BACKGROUND: Skeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation. Muscle atrophy is characterized as reduction of muscle fiber size and loss of muscle mass while muscle fibrosis is due to fibroblasts activation and excessive production of extracellular matrix. Purinergic receptor P2Y2 has been implicated in fibrosis. This study aims to elucidate the roles of P2Y2 in sleketal muscle atrophy and fibrosis. METHODS: Primary muscle fibroblasts were isolated from wild type and P2Y2 knockout (KO) mice and their proliferating and migrating abilities were assessed by CCK-8 and Transwell migration assays respectively. Fibroblasts were activated with TGF-ß1 and assessed by western blot of myofibroblast markers including α-SMA, CTGF, and collagen I. Muscle atrophy and fibrosis were induced by transection of distal sciatic nerve and assessed using Masson staining. RESULTS: P2Y2 KO fibroblasts proliferated and migrated significantly slower than WT fibroblasts with or without TGF-ß1.The proliferation and ECM production were enhanced by P2Y2 agonist PSB-1114 and inhibited by antagonist AR-C118925. TGF-ß1 induced fibrotic activation was abolished by P2Y2 ablation and inhibited by AKT, ERK, and PKC inhibitors. Ablation of P2Y2 reduced denervation induced muscle atrophy and fibrosis. CONCLUSIONS: P2Y2 is a promoter of skeletal muscle atrophy and activation of fibroblasts after muscle injury, which signaling through AKT, ERK and PKC. P2Y2 could be a potential intervention target after muscle injury.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/patologia , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores Purinérgicos P2Y2/metabolismo , Animais , Células Cultivadas , Fibroblastos/patologia , Fibrose , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
11.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360722

RESUMO

Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a 'rewired' metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.


Assuntos
Envelhecimento/metabolismo , Arginina/metabolismo , Lisina/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Transdução de Sinais , Envelhecimento/patologia , Animais , Masculino , Camundongos , Músculo Esquelético/patologia
12.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360780

RESUMO

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.


Assuntos
Ativadores de Enzimas/farmacologia , Músculo Esquelético/enzimologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Animais , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/enzimologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia
13.
Medicine (Baltimore) ; 100(34): e27011, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449472

RESUMO

RATIONALE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Common sites for metastasis are the liver and peritoneum, whereas skeletal muscle metastases are rare. PATIENT CONCERNS: A 59-year-old man with skeletal muscle metastasis was diagnosed during a period of adjuvant imatinib therapy following the recurrence of GIST of the small intestine. DIAGNOSIS: The patient was diagnosed with skeletal muscle metastasis of GIST based on immunohistochemistry and molecular pathology analysis results. INTERVENTION: Extensive resection of the left thigh tumor was performed. The patient underwent whole-exome sequencing of tissue examination. The results suggest that resistance to imatinib may have been developed, and the patient was therefore administered sunitinib instead. OUTCOMES: Complete remission was observed following sunitinib therapy. LESSONS: In cases of skeletal muscle metastasis diagnosed during a period of adjuvant imatinib therapy following the recurrence of a GIST of the small intestine, whole exome sequencing may be used to discover more gene variations.


Assuntos
Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Neoplasias Musculares/secundário , Músculo Esquelético/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/tratamento farmacológico , Neoplasias Musculares/cirurgia , Sunitinibe/uso terapêutico , Coxa da Perna/patologia , Sequenciamento Completo do Exoma
14.
Undersea Hyperb Med ; 48(3): 227-238, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34390627

RESUMO

Background: The optimal timing of hyperbaric oxygen (HBO2) treatments for the best recovery following muscle injury has yet to be determined. Thus, the optimal number and timing of HBO2 treatments for maximal muscle regeneration were explored. Methods: The HBO2 treatment protocol consisted of 2.5 ATA 100% oxygen for 120 minutes. Muscle-injured rats were randomized to one of 10 groups: single HBO2 treatment immediately after injury (HBO 1T day 0), one day (HBO 1T day 1), three days (HBO 1T day 3) and five days (HBO 1T day 5) after injury; three HBO2 treatments from immediately after injury to two days after injury (HBO 3T day 0-2), from one to three days after injury (HBO 3T day 1-3), from three to five days after injury (HBO 3T day 3-5), from five to seven days after injury (HBO 3T day 5-7); five daily HBO2 treatments (HBO 5T); and no treatment (NT). Results: HBO 5T and HBO 3T day 0-2, days 1-3 and days 3-5 significantly promoted CD206-positive cell infiltration, satellite cell differentiation and muscle regeneration compared to the NT group. Conclusion: Five HBO2 treatments and three HBO2 treatments within three days of injury promote muscle regeneration.


Assuntos
Contusões/terapia , Oxigenação Hiperbárica/métodos , Músculo Esquelético/lesões , Células Satélites de Músculo Esquelético/fisiologia , Tempo para o Tratamento , Cicatrização/fisiologia , Animais , Diferenciação Celular , Proliferação de Células/fisiologia , Contusões/fisiopatologia , Oxigenação Hiperbárica/estatística & dados numéricos , Macrófagos/fisiologia , Masculino , Contração Muscular/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiologia , Projetos Piloto , Distribuição Aleatória , Ratos , Ratos Wistar
15.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361076

RESUMO

The weight of skeletal muscle accounts for approximately 40% of the whole weight in a healthy individual, and the normal metabolism and motor function of the muscle are indispensable for healthy life. In addition, the skeletal muscle of the maxillofacial region plays an important role not only in eating and swallowing, but also in communication, such as facial expressions and conversations. In recent years, skeletal muscle atrophy has received worldwide attention as a serious health problem. However, the mechanism of skeletal muscle atrophy that has been clarified at present is insufficient, and a therapeutic method against skeletal muscle atrophy has not been established. This review provides views on the importance of skeletal muscle in the maxillofacial region and explains the differences between skeletal muscles in the maxillofacial region and other regions. We summarize the findings to change in gene expression in muscle remodeling and emphasize the advantages and disadvantages of denervation-induced skeletal muscle atrophy model. Finally, we discuss the newly discovered beneficial effects of natural compounds on skeletal muscle atrophy.


Assuntos
Produtos Biológicos/farmacologia , Denervação/efeitos adversos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Animais , Humanos , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia
16.
Ageing Res Rev ; 70: 101398, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34214642

RESUMO

Myosteatosis, which is excessive fat infiltration in the skeletal muscle, is now considered a distinct disease from sarcopenia. Advances in imaging technique have made muscle parameters an evaluable biomarker, and many studies have proved association between myosteatosis and aging or disease process. However, the diagnosis and clinical impact of myosteatosis have not been well established. Thus, we aim to provide a systematic summary with a qualitive review of 73 eligible studies regarding these issues. First, the most widely used modality to diagnose myosteatosis is abdominal computed tomography, based on evaluation of the muscle radiodensity of the total abdominal muscle area predominantly at the L3 vertebral level. However, there was significant heterogeneity in the diagnostic methods and cutoff values used to diagnose myosteatosis (32 different cutoff values among 73 studies). Second, the clinical impact of myosteatosis on prognosis was very straightforward, and most studies have shown a negative impact of myosteatosis on overall survival and complications related to underlying diseases. However, the mechanism of the myosteatosis on mortality has not been explored well, and metabolic dysfunction (i.e. insulin resistance, systemic inflammation) would be a possible explanation. Providing systemic review of current issues can elucidate future directions for developing standardized diagnosis and management of myosteatosis.


Assuntos
Sarcopenia , Composição Corporal , Humanos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Prognóstico , Sarcopenia/diagnóstico por imagem , Sarcopenia/patologia , Tomografia Computadorizada por Raios X
17.
Nutrients ; 13(6)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200533

RESUMO

Aging and osteoarthritis are associated with high risk of muscle mass loss, which leads to physical disability; this loss can be effectively alleviated by diet (DI) and exercise (ET) interventions. This study investigated the relative effects of different types of diet, exercise, and combined treatment (DI+ET) on muscle mass and functional outcomes in individuals with obesity and lower-limb osteoarthritis. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) examining the efficacy of DI, ET, and DI+ET in patients with obesity and lower-extremity osteoarthritis. The included RCTs were analyzed through network meta-analysis and risk-of-bias assessment. We finally included 34 RCTs with a median (range/total) Physiotherapy Evidence Database score of 6.5 (4-8/10). DI plus resistance ET, resistance ET alone, and aerobic ET alone were ranked as the most effective treatments for increasing muscle mass (standard mean difference (SMD) = 1.40), muscle strength (SMD = 1.93), and walking speed (SMD = 0.46). Our findings suggest that DI+ET is beneficial overall for muscle mass in overweight or obese adults with lower-limb osteoarthritis, especially those who are undergoing weight management.


Assuntos
Exercício Físico/fisiologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Osteoartrite/complicações , Sobrepeso/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcopenia/complicações , Adulto , Idoso , Dieta , Seguimentos , Humanos , Pessoa de Meia-Idade , Força Muscular/fisiologia , Tamanho do Órgão , Osteoartrite/fisiopatologia , Sobrepeso/fisiopatologia , Viés de Publicação , Análise de Regressão , Risco , Sarcopenia/fisiopatologia , Resultado do Tratamento , Caminhada/fisiologia
18.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202899

RESUMO

The biomechanical parameters of muscle soleus contraction in rats and their blood biochemical indicators after the intramuscular administration of water-soluble C60 fullerene at doses of 0.5, 1, and 2 mg/kg 1 h before the onset of muscle ischemia were investigated. In particular, changes in the contraction force of the ischemic muscle soleus, the integrated power of the muscle, the time to achieve the maximum force response, the dynamics of fatigue processes, and the parameters of the transition from dentate to smooth tetanus, levels of creatinine, creatine kinase, lactate and lactate dehydrogenase, and parameters of prooxidant-antioxidant balance (thiobarbituric acid reactive substances, hydrogen peroxide, and reduced glutathione and catalase) were analyzed. The positive therapeutic changes in the studied biomechanical and biochemical markers were revealed, which indicate the possibility of using water-soluble C60 fullerenes as effective prophylactic nanoagents to reduce the severity of pathological conditions of the muscular system caused by ischemic damage to skeletal muscles.


Assuntos
Materiais Biocompatíveis/química , Fulerenos/química , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Nanopartículas/química , Substâncias Protetoras/química , Animais , Materiais Biocompatíveis/farmacologia , Biomarcadores/sangue , Fenômenos Biomecânicos , Fenômenos Químicos , Modelos Animais de Doenças , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
19.
Eur J Oncol Nurs ; 53: 101943, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281789

RESUMO

PURPOSE: Our study aims to investigate dietary intake characteristics and their association with skeletal muscle mass in head and neck cancer patients treated with radiotherapy. METHODS: From March 2017 to August 2018, patients with head and neck cancer who received radiotherapy at our affiliated hospital were enrolled. Dietary intake was assessed through 24-hr dietary recall and skeletal muscle mass was evaluated by bioelectrical impedance analysis at three-time points. Appendicular skeletal muscle mass was adjusted for height squared defined sarcopenia and correlated with dietary intake by generalized estimating equations (GEE). RESULTS: This study sample comprised 287 patients [median age: 54 years; 187 (65.2%) men]. Median dietary intake at post-treatment was 14.95 kcal/kg/day energy and 0.63 g/kg/day protein. Skeletal muscle mass decreased significantly in all patients. The prevalence of sarcopenia increased from 24.4% before treatment to 46.7% at the end of treatment. Exploratory univariate GEE analysis revealed that radiotherapy time-point, male-gender, age ≥60 and decreased dietary energy intake significantly impacted on muscle loss represented by the appendicular skeletal muscle index. After controlling covariates, dietary energy intake was only positively associated with muscle loss in women (P = 0.013, 95% CI = 0.003-0.027) but not in men (P = 0.788, 95% CI = -0.007-0.009). CONCLUSION: While the loss in skeletal muscle is more prevalent in men receiving radiotherapy, the effects of dietary energy intake were only associated with women. A prospective randomized clinical trial is required to identify the appropriate amount of dietary energy supplement by gender in cancer patients treated with radiotherapy.


Assuntos
Neoplasias de Cabeça e Pescoço , Sarcopenia , Ingestão de Alimentos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Prevalência , Estudos Prospectivos , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Sarcopenia/patologia
20.
Eur J Radiol ; 142: 109834, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252866

RESUMO

BACKGROUND: Body composition is associated with mortality; however its routine assessment is too time-consuming. PURPOSE: To demonstrate the value of artificial intelligence (AI) to extract body composition measures from routine studies, we aimed to develop a fully automated AI approach to measure fat and muscles masses, to validate its clinical discriminatory value, and to provide the code, training data and workflow solutions to facilitate its integration into local practice. METHODS: We developed a neural network that quantified the tissue components at the L3 vertebral body level using data from the Liver Tumor Challenge (LiTS) and a pancreatic cancer cohort. We classified sarcopenia using accepted skeletal muscle index cut-offs and visceral fat based its median value. We used Kaplan Meier curves and Cox regression analysis to assess the association between these measures and mortality. RESULTS: Applying the algorithm trained on LiTS data to the local cohort yielded good agreement [>0.8 intraclass correlation (ICC)]; when trained on both datasets, it had excellent agreement (>0.9 ICC). The pancreatic cancer cohort had 136 patients (mean age: 67 ± 11 years; 54% women); 15% had sarcopenia; mean visceral fat was 142 cm2. Concurrent with prior research, we found a significant association between sarcopenia and mortality [mean survival of 15 ± 12 vs. 22 ± 12 (p < 0.05), adjusted HR of 1.58 (95% CI: 1.03-3.33)] but no association between visceral fat and mortality. The detector analysis took 1 ± 0.5 s. CONCLUSIONS: AI body composition analysis can provide meaningful imaging biomarkers from routine exams demonstrating AI's ability to further enhance the clinical value of radiology reports.


Assuntos
Neoplasias Pancreáticas , Sarcopenia , Idoso , Inteligência Artificial , Composição Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Sarcopenia/patologia , Tomografia Computadorizada por Raios X
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