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1.
Mol Cell ; 81(9): 2041-2052.e6, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823141

RESUMO

Cellular senescence is a state of stable proliferative arrest triggered by damaging signals. Senescent cells persist during aging and promote age-related pathologies via the pro-inflammatory senescence-associated secretory phenotype (SASP), whose regulation depends on environmental factors. In vivo, a major environmental variable is oxygenation, which varies among and within tissues. Here, we demonstrate that senescent cells express lower levels of detrimental pro-inflammatory SASP factors in physiologically hypoxic environments, as measured in culture and in tissues. Mechanistically, exposure of senescent cells to low-oxygen conditions leads to AMPK activation and AMPK-mediated suppression of the mTOR-NF-κB signaling loop. Finally, we demonstrate that treatment with hypoxia-mimetic compounds reduces SASP in cells and tissues and improves strength in chemotherapy-treated and aged mice. Our findings highlight the importance of oxygen as a determinant for pro-inflammatory SASP expression and offer a potential new strategy to reduce detrimental paracrine effects of senescent cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proliferação de Células , Senescência Celular , Hipóxia/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Fatores Etários , Animais , Antibióticos Antineoplásicos/farmacologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Hidroxibenzoatos/farmacologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Mediadores da Inflamação/metabolismo , Isoquinolinas/farmacologia , Camundongos Endogâmicos C57BL , Força Muscular , NF-kappa B/metabolismo , Comunicação Parácrina , Fenótipo , Transdução de Sinais
2.
Hepatology ; 80(5): 1134-1146, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38456800

RESUMO

BACKGROUND AND AIMS: Most patients with decompensated cirrhosis fail to meet their nutrition targets. The impact of nasogastric feeding (NGF) on malnutrition in cirrhosis remains unknown. This study aims to assess the impact of pretransplant NGF on pre-liver transplant and post-liver transplant outcomes. APPROACH AND RESULTS: This single-center, prospective randomized controlled trial of 55 patients with severe malnutrition and low handgrip strength (HGS) compared a standard high-energy high-protein diet to diet plus supplemental nocturnal NGF while awaiting transplant. The primary outcome was a change in HGS. The median age was 58.5 years (IQR: 51.1-64), median MELD was 24 (20-28.5), and 32 (58%) patients were male. The median duration of NGF was 63.0 days (34.5-127), following which time the median between-group difference in HGS was 3.6 kg (95% CI: 1.7-5.2, p <0.001), an increase of 20% from baseline. Mid-upper-arm circumference, triceps skinfold, and immune function all increased significantly with NGF. Muscle and nutritional parameters continued to improve with increasing duration of feeding. NGF significantly increased daily energy intake between groups by 1285 kcal (95% CI: 860-1677) and protein intake by 51 g (95% CI: 32-71) (both p <0.001). All NGF patients met >100% of their measured nutritional requirements. Posttransplant clinical outcomes were similar between groups. CONCLUSIONS: Targeted enteral feeding before liver transplant improves HGS, anthropometry, and immune function in severely malnourished patients with cirrhosis. These findings provide a strong rationale for early consideration of NGF to reverse malnutrition and improve muscle strength. Appropriately powered studies should explore whether NGF can also impact clinically relevant outcomes including pretransplant and posttransplant mortality.


Assuntos
Nutrição Enteral , Cirrose Hepática , Transplante de Fígado , Desnutrição , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Nutrição Enteral/métodos , Estudos Prospectivos , Desnutrição/etiologia , Desnutrição/prevenção & controle , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Força da Mão , Listas de Espera , Força Muscular , Resultado do Tratamento
3.
FASEB J ; 38(13): e23784, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38953567

RESUMO

To investigate the effects of heavy-load strength training during (neo-)adjuvant chemotherapy in women with breast cancer on muscle strength, body composition, muscle fiber size, satellite cells, and myonuclei. Women with stage I-III breast cancer were randomly assigned to a strength training group (ST, n = 23) performing supervised heavy-load strength training twice a week during chemotherapy, or a usual care control group (CON, n = 17). Muscle strength and body composition were measured and biopsies from m. vastus lateralis collected before the first cycle of chemotherapy (T0) and after chemotherapy and training (T1). Muscle strength increased significantly more in ST than in CON in chest-press (ST: +10 ± 8%, p < .001, CON: -3 ± 5%, p = .023) and leg-press (ST: +11 ± 8%, p < .001, CON: +3 ± 6%, p = .137). Both groups reduced fat-free mass (ST: -4.9 ± 4.0%, p < .001, CON: -5.2 ± 4.9%, p = .004), and increased fat mass (ST: +15.3 ± 16.5%, p < .001, CON: +16.3 ± 19.8%, p = .015) with no significant differences between groups. No significant changes from T0 to T1 and no significant differences between groups were observed in muscle fiber size. For myonuclei per fiber a non-statistically significant increase in CON and a non-statistically significant decrease in ST in type I fibers tended (p = .053) to be different between groups. Satellite cells tended to decrease in ST (type I: -14 ± 36%, p = .097, type II: -9 ± 55%, p = .084), with no changes in CON and no differences between groups. Strength training during chemotherapy improved muscle strength but did not significantly affect body composition, muscle fiber size, numbers of satellite cells, and myonuclei compared to usual care.


Assuntos
Neoplasias da Mama , Força Muscular , Treinamento Resistido , Células Satélites de Músculo Esquelético , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Treinamento Resistido/métodos , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Pessoa de Meia-Idade , Adulto , Quimioterapia Adjuvante , Composição Corporal , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Terapia Neoadjuvante , Idoso
4.
Mol Ther ; 32(8): 2604-2623, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-38910327

RESUMO

Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. To reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRPP448L mice with a dual FKRP/FST gene therapy packaged into a single adeno-associated virus (AAV) vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a 1-h walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with single AAV-bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.


Assuntos
Dependovirus , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos , Força Muscular , Músculo Esquelético , Pentosiltransferases , Animais , Camundongos , Terapia Genética/métodos , Força Muscular/genética , Dependovirus/genética , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Expressão Gênica , Caminhada , Humanos , Regulação da Expressão Gênica
5.
Proc Natl Acad Sci U S A ; 119(24): e2103615119, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35671424

RESUMO

Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models-Myogenic factor 5 (Myf5)-Arf-like Protein 3 (Arl3)-/-, Paired box protein Pax-7 (Pax7)-Intraflagellar transport protein 88 homolog (Ift88)-/-, and Pax7-Arl3-/--by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3-/- mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3-/- and Pax7-Arl3-/- mice or primary isolated Myf5-Arl3-/- and Pax7-Ift88-/- myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.


Assuntos
Cílios , Força Muscular , Condicionamento Físico Animal , Células Satélites de Músculo Esquelético , Animais , Diferenciação Celular , Cílios/fisiologia , Terapia por Exercício , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/fisiologia
6.
J Physiol ; 602(15): 3641-3660, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38980963

RESUMO

Limited knowledge exists regarding the chronic effect of muscular exercise on muscle function in a murine model of severe Duchenne muscular dystrophy (DMD). Here we determined the effects of 1 month of voluntary wheel running (WR), 1 month of enforced treadmill running (TR) and 1 month of mechanical overloading resulting from the removal of the synergic muscles (OVL) in mice lacking both dystrophin and desmin (DKO). Additionally, we examined the effect of activin receptor administration (AR). DKO mice, displaying severe muscle weakness, atrophy and greater susceptibility to contraction-induced functional loss, were exercised or treated with AR at 1 month of age and in situ force production of lower leg muscle was measured at the age of 2 months. We found that TR and OVL increased absolute maximal force and the rate of force development of the plantaris muscle in DKO mice. In contrast, those of the tibialis anterior (TA) muscle remained unaffected by TR and WR. Furthermore, the effects of TR and OVL on plantaris muscle function in DKO mice closely resembled those in mdx mice, a less severe murine DMD model. AR also improved absolute maximal force and the rate of force development of the TA muscle in DKO mice. In conclusion, exercise training improved plantaris muscle weakness in severely affected dystrophic mice. Consequently, these preclinical results may contribute to fostering further investigations aimed at assessing the potential benefits of exercise for DMD patients, particularly resistance training involving a low number of intense muscle contractions. KEY POINTS: Very little is known about the effects of exercise training in a murine model of severe Duchenne muscular dystrophy (DMD). One reason is that it is feared that chronic muscular exercise, particularly that involving intense muscle contractions, could exacerbate the disease. In DKO mice lacking both dystrophin and desmin, characterized by severe lower leg muscle weakness, atrophy and fragility in comparison to the less severe DMD mdx model, we found that enforced treadmill running improved absolute maximal force of the plantaris muscle, while that of tibialis anterior muscle remained unaffected by both enforced treadmill and voluntary wheel running. Furthermore, mechanical overloading, a non-physiological model of chronic resistance exercise, reversed plantaris muscle weakness. Consequently, our findings may have the potential to alleviate concerns and pave the way for exploring the prescription of endurance and resistance training as a viable therapeutic approach for the treatment of dystrophic patients. Additionally, such interventions may serve in mitigating the pathophysiological mechanisms induced by physical inactivity.


Assuntos
Desmina , Distrofina , Músculo Esquelético , Condicionamento Físico Animal , Corrida , Animais , Masculino , Camundongos , Desmina/genética , Desmina/metabolismo , Distrofina/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Knockout , Contração Muscular , Força Muscular , Músculo Esquelético/fisiologia , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Corrida/fisiologia
7.
J Physiol ; 602(19): 4929-4939, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39216089

RESUMO

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P < 0.0001 and r = 0.764, P < 0.0001 respectively). The age-associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non-ambulant subjects, suggesting a threshold of 18-22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. KEY POINTS: The non-invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non-ambulant patients. The difference in %MM between ambulant and non-ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM. The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability.


Assuntos
Músculo Esquelético , Distrofia Muscular de Duchenne , Caminhada , Humanos , Distrofia Muscular de Duchenne/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/urina , Adolescente , Criança , Músculo Esquelético/fisiopatologia , Masculino , Pré-Escolar , Adulto Jovem , Caminhada/fisiologia , Feminino , Estudos Longitudinais , Creatina/urina , Creatinina/urina , Força Muscular , Adulto
8.
J Physiol ; 602(12): 2839-2854, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38748517

RESUMO

Loss of muscle mass and function induced by sepsis contributes to physical inactivity and disability in intensive care unit patients. Limiting skeletal muscle deconditioning may thus be helpful in reducing the long-term effect of muscle wasting in patients. We tested the hypothesis that invalidation of the myostatin gene, which encodes a powerful negative regulator of skeletal muscle mass, could prevent or attenuate skeletal muscle wasting and improve survival of septic mice. Sepsis was induced by caecal ligature and puncture (CLP) in 13-week-old C57BL/6J wild-type and myostatin knock-out male mice. Survival rates were similar in wild-type and myostatin knock-out mice seven days after CLP. Loss in muscle mass was also similar in wild-type and myostatin knock-out mice 4 and 7 days after CLP. The loss in muscle mass was molecularly supported by an increase in the transcript level of E3-ubiquitin ligases and autophagy-lysosome markers. This transcriptional response was blunted in myostatin knock-out mice. No change was observed in the protein level of markers of the anabolic insulin/IGF1-Akt-mTOR pathway. Muscle strength was similarly decreased in wild-type and myostatin knock-out mice 4 and 7 days after CLP. This was associated with a modified expression of genes involved in ion homeostasis and excitation-contraction coupling, suggesting that a long-term functional recovery following experimental sepsis may be impaired by a dysregulated expression of molecular determinants of ion homeostasis and excitation-contraction coupling. In conclusion, myostatin gene invalidation does not provide any benefit in preventing skeletal muscle mass loss and strength in response to experimental sepsis. KEY POINTS: Survival rates are similar in wild-type and myostatin knock-out mice seven days after the induction of sepsis. Loss in muscle mass and muscle strength are similar in wild-type and myostatin knock-out mice 4 and 7 days after the induction of an experimental sepsis. Despite evidence of a transcriptional regulation, the protein level of markers of the anabolic insulin/IGF1-Akt-mTOR pathway remained unchanged. RT-qPCR analysis of autophagy-lysosome pathway markers indicates that activity of the pathway may be altered by experimental sepsis in wild-type and myostatin knock-out mice. Experimental sepsis induces greater variations in the mRNA levels of wild-type mice than those of myostatin knock-out mice, without providing any significant catabolic resistance or functional benefits.


Assuntos
Músculo Esquelético , Miostatina , Sepse , Animais , Masculino , Camundongos , Autofagia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Força Muscular , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Miostatina/genética , Miostatina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Sepse/genética , Sepse/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética
9.
Circulation ; 147(20): 1534-1553, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37186680

RESUMO

Sarcopenia is the loss of muscle strength, mass, and function, which is often exacerbated by chronic comorbidities including cardiovascular diseases, chronic kidney disease, and cancer. Sarcopenia is associated with faster progression of cardiovascular diseases and higher risk of mortality, falls, and reduced quality of life, particularly among older adults. Although the pathophysiologic mechanisms are complex, the broad underlying cause of sarcopenia includes an imbalance between anabolic and catabolic muscle homeostasis with or without neuronal degeneration. The intrinsic molecular mechanisms of aging, chronic illness, malnutrition, and immobility are associated with the development of sarcopenia. Screening and testing for sarcopenia may be particularly important among those with chronic disease states. Early recognition of sarcopenia is important because it can provide an opportunity for interventions to reverse or delay the progression of muscle disorder, which may ultimately impact cardiovascular outcomes. Relying on body mass index is not useful for screening because many patients will have sarcopenic obesity, a particularly important phenotype among older cardiac patients. In this review, we aimed to: (1) provide a definition of sarcopenia within the context of muscle wasting disorders; (2) summarize the associations between sarcopenia and different cardiovascular diseases; (3) highlight an approach for a diagnostic evaluation; (4) discuss management strategies for sarcopenia; and (5) outline key gaps in knowledge with implications for the future of the field.


Assuntos
Doenças Cardiovasculares , Sarcopenia , Humanos , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/terapia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Qualidade de Vida , Composição Corporal , Força Muscular/fisiologia , Músculo Esquelético/metabolismo
10.
Pflugers Arch ; 476(8): 1221-1233, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38916665

RESUMO

This study investigated the effect of a resistance training (RT) period at terrestrial (HH) and normobaric hypoxia (NH) on both muscle hypertrophy and maximal strength development with respect to the same training in normoxia (N). Thirty-three strength-trained males were assigned to N (FiO2 = 20.9%), HH (2,320 m asl) or NH (FiO2 = 15.9%). The participants completed an 8-week RT program (3 sessions/week) of a full body routine. Muscle thickness of the lower limb and 1RM in back squat were assessed before and after the training program. Blood markers of stress, inflammation (IL-6) and muscle growth (% active mTOR, myostatin and miRNA-206) were measured before and after the first and last session of the program. Findings revealed all groups improved 1RM, though this was most enhanced by RT in NH (p = 0.026). According to the moderate to large excess of the exercise-induced stress response (lactate and Ca2+) in HH and N, results only displayed increases in muscle thickness in these two conditions over NH (ES > 1.22). Compared with the rest of the environmental conditions, small to large increments in % active mTOR were only found in HH, and IL-6, myostatin and miR-206 in NH throughout the training period. In conclusion, the results do not support the expected additional benefit of RT under hypoxia compared to N on muscle growth, although it seems to favour gains in strength. The greater muscle growth achieved in HH over NH confirms the impact of the type of hypoxia on the outcomes.


Assuntos
Hipóxia , Força Muscular , Músculo Esquelético , Miostatina , Treinamento Resistido , Masculino , Humanos , Treinamento Resistido/métodos , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Miostatina/metabolismo , Adulto , Força Muscular/fisiologia , MicroRNAs/metabolismo , MicroRNAs/genética , Serina-Treonina Quinases TOR/metabolismo , Interleucina-6/metabolismo , Interleucina-6/sangue , Adulto Jovem , Desenvolvimento Muscular
11.
Am J Physiol Lung Cell Mol Physiol ; 326(6): L713-L726, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38469649

RESUMO

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.


Assuntos
Resistência das Vias Respiratórias , Diafragma , Mucopolissacaridose III , Alvéolos Pulmonares , Animais , Diafragma/fisiopatologia , Diafragma/patologia , Diafragma/metabolismo , Complacência Pulmonar , Camundongos , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/fisiopatologia , Alvéolos Pulmonares/metabolismo , Mucopolissacaridose III/patologia , Mucopolissacaridose III/fisiopatologia , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/genética , Contração Muscular/fisiologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Força Muscular , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/metabolismo , Masculino
12.
J Neurophysiol ; 132(2): 527-530, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38985940

RESUMO

Ischemic preconditioning (IPC) can enhance maximal strength likely due to neural priming. Cruz et al. (Cruz R, Tramontin AF, Oliveira AS, Caputo F, Denadai BS, Greco CC. Scand J Med Sci Sports 34: e14591, 2024) examined the neurophysiological mechanisms responsible for the ergogenic effect. Although key neurophysiological measures remained largely unchanged, voluntary activation and maximal strength were greater following IPC than sham-IPC. Although the mechanistic evidence remains inconclusive, the greater maximal strength provides further evidence of the ergogenic benefit of IPC. Researchers should continue examining the broader functional implications of IPC.


Assuntos
Precondicionamento Isquêmico , Precondicionamento Isquêmico/métodos , Humanos , Força Muscular/fisiologia , Músculo Esquelético/fisiologia
13.
J Neurophysiol ; 132(2): 470-484, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38985941

RESUMO

Following events such as fatigue or stroke, individuals often move their trunks forward during reaching, leveraging a broader muscle group even when only arm movement would suffice. In previous work, we showed the existence of a "force reserve": a phenomenon where individuals, when challenged with a heavy weight, adjusted their motor coordination to preserve approximately 40% of their shoulder's force. Here, we investigated if such reserve can predict hip, shoulder, and elbow movements and torques resulting from an induced shoulder strength deficit. We engaged 20 healthy participants in a reaching task with incrementally heavier dumbbells, analyzing arm and trunk movements via motion capture and joint torques through inverse dynamics. We simulated these movements using an optimal control model of a 3-degree-of-freedom upper body, contrasting three cost functions: traditional sum of squared torques, a force reserve function incorporating a nonlinear penalty, and a normalized torque function. Our results demonstrate a clear increase in trunk movement correlated with heavier dumbbell weights, with participants employing compensatory movements to maintain a shoulder force reserve of approximately 40% of maximum torque. Simulations showed that while traditional and reserve functions accurately predicted trunk compensation, only the reserve function effectively predicted joint torques under heavier weights. These findings suggest that compensatory movements are strategically employed to minimize shoulder effort and distribute load across multiple joints in response to weakness. We discuss the implications of the force reserve cost function in the context of optimal control of human movements and its relevance for understanding compensatory movements poststroke.NEW & NOTEWORTHY Our study reveals key findings on compensatory movements during upper limb reaching tasks under shoulder strength deficits, as observed poststroke. Using heavy dumbbells with healthy volunteers, we demonstrate how forward trunk displacement conserves around 40% of shoulder strength reserve during reaching. We show that an optimal controller employing a cost function combining squared motor torque and a nonlinear penalty for excessive muscle activation outperforms traditional controllers in predicting torques and compensatory movements in these scenarios.


Assuntos
Movimento , Ombro , Torque , Humanos , Masculino , Feminino , Adulto , Ombro/fisiologia , Movimento/fisiologia , Força Muscular/fisiologia , Fenômenos Biomecânicos/fisiologia , Adulto Jovem , Músculo Esquelético/fisiologia , Desempenho Psicomotor/fisiologia , Braço/fisiologia , Tronco/fisiologia
14.
Eur J Neurosci ; 59(9): 2336-2352, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38419404

RESUMO

The rapid increase in strength following strength-training involves neural adaptations, however, their specific localisation remains elusive. Prior focus on corticospinal responses prompts this study to explore the understudied cortical/subcortical adaptations, particularly cortico-reticulospinal tract responses, comparing healthy strength-trained adults to untrained peers. Fifteen chronically strength-trained individuals (≥2 years of training, mean age: 24 ± 7 years) were compared with 11 age-matched untrained participants (mean age: 26 ± 8 years). Assessments included maximal voluntary force (MVF), corticospinal excitability using transcranial magnetic stimulation (TMS), spinal excitability (cervicomedullary stimulation), voluntary activation (VA) and reticulospinal tract (RST) excitability, utilizing StartReact responses and ipsilateral motor-evoked potentials (iMEPs) for the flexor carpi radialis muscle. Trained participants had higher normalized MVF (6.4 ± 1.1 N/kg) than the untrained participants (4.8 ± 1.3 N/kg) (p = .003). Intracortical facilitation was higher in the strength-trained group (156 ± 49%) (p = .02), along with greater VA (98 ± 3.2%) (p = .002). The strength-trained group displayed reduced short-interval-intracortical inhibition (88 ± 8.0%) compared with the untrained group (69 ± 17.5%) (p < .001). Strength-trained individuals exhibited a greater normalized rate of force development (38.8 ± 10.1 N·s-1/kg) (p < .009), greater reticulospinal gain (2.5 ± 1.4) (p = .02) and higher ipsilateral-to-contralateral MEP ratios compared with the untrained group (p = .03). Strength-trained individuals displayed greater excitability within the intrinsic connections of the primary motor cortex and the RST. These results suggest greater synaptic input from the descending cortico-reticulospinal tract to α-motoneurons in strength-trained individuals, thereby contributing to the observed increase in VA and MVF.


Assuntos
Potencial Evocado Motor , Músculo Esquelético , Tratos Piramidais , Treinamento Resistido , Estimulação Magnética Transcraniana , Humanos , Adulto , Masculino , Potencial Evocado Motor/fisiologia , Feminino , Estimulação Magnética Transcraniana/métodos , Tratos Piramidais/fisiologia , Treinamento Resistido/métodos , Músculo Esquelético/fisiologia , Adulto Jovem , Córtex Motor/fisiologia , Força Muscular/fisiologia , Adaptação Fisiológica/fisiologia , Eletromiografia
15.
Eur J Neurosci ; 59(2): 298-307, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38128061

RESUMO

Children with cerebral palsy (CP) exhibit impaired motor control and significant muscle weakness due to a brain lesion. However, studies that assess the relationship between brain activity and performance on dynamic functional muscle strength assessments in CP are needed. The aim of this study was to determine the effect of a progressive lateral step-up test on prefrontal cortex (PFC) hemodynamic activity in children with CP. Fourteen ambulatory children with spastic CP (Gross Motor Function Classification System level I; 5-11 y) and 14 age- and sex-matched typically developing control children completed a progressive lateral step-up test at incremental step heights (0, 10, 15 and 20 cm) using their non-dominant lower limb. Hemodynamic activity in the PFC was assessed using non-invasive, portable functional neuroimaging (functional near-infrared spectroscopy). Children with CP completed fewer repetitions at each step height and exhibited lower PFC hemodynamic activity across step heights compared to controls. Lower PFC activation in CP was maintained after statistically controlling for the number of repetitions completed at each step height. PFC hemodynamic activity was not associated with LSUT task performance in children with CP, but a positive relationship was observed in controls at the most challenging 20 cm step height. The results suggest there is an altered PFC recruitment pattern in children with CP during a highly dynamic test of functional strength. Further studies are needed to explore the mechanisms underlying the suppressed PFC activation observed in children with CP compared to typically developing children.


Assuntos
Paralisia Cerebral , Criança , Humanos , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/patologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Extremidade Inferior , Córtex Pré-Frontal/fisiologia , Hemodinâmica , Força Muscular/fisiologia
16.
Annu Rev Med ; 73: 377-391, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-34794323

RESUMO

The global population is rapidly aging, with predictions of many more people living beyond 85 years. Age-related physiological adaptations predispose to decrements in physical function and functional capacity, the rate of which can be accelerated by chronic disease and prolonged physical inactivity. Decrements in physical function exacerbate the risk of chronic disease, disability, dependency, and frailty with advancing age. Regular exercise positively influences health status, physical function, and disease risk in adults of all ages. Herein, we review the role of structured exercise training in the oldest old on cardiorespiratory fitness and muscular strength and power, attributes critical for physical function, mobility, and independent living.


Assuntos
Exercício Físico , Octogenários , Adulto , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Terapia por Exercício , Humanos , Força Muscular/fisiologia
17.
Oncologist ; 29(6): e828-e836, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38206849

RESUMO

BACKGROUND: Feasibility of exercise in patients with metastatic cancer is still a challenge. This study aimed to determine the feasibility and preliminary efficacy of an exercise intervention based on a patient-preferred delivery mode in patients affected by metastatic cancer. MATERIALS AND METHODS: Forty-four patients with a confirmed diagnosis of metastatic cancer were recruited in a 3-month exercise program. Whereas the exercise program consisted of aerobic and resistance activities performed twice a week, the participants may choose the mode of delivery: home based, personal training, or group based. The primary endpoint was the feasibility, defined by recruitment rate, attendance, adherence, dropout rate, tolerability (comparing the session RPE with the target RPE), and safety (using the Common Terminology Criteria for Adverse Events, version 5.0). Secondary endpoints included cardiorespiratory fitness (six minutes walking test), muscle strength (handgrip strength test and isometric leg press test), flexibility (the back scratch and chair sit and reach tests), anthropometric parameters (body mass index and waist-hip ratio), quality of life (EORTC QLQ C-30 questionnaire), and amount of physical exercise (Godin's Shepard Leisure Time Exercise Questionnaire). Descriptive statistics, Student t test, and Wilcoxon signed rank test were used to analyze data. RESULTS: The study recruitment rate was 81%. Out of 44 recruited patients, 28 chose the personal training program, 16 chose the home-based program, and none chose the group-based program. Nine dropouts occurred (20%), 6 in the personal training program, and 3 in the home-based intervention. The median attendance rate was 92%, adherence was 88%, tolerability was 100%, and 9 nonsevere adverse events were registered during the exercise sessions. An increase in cardiorespiratory fitness (P < .001) and flexibility (P = .011 for chair sit and reach; P = .040 for back scratch) was observed at the end of the intervention, while no changes in anthropometric values and muscle strength were detected. Different quality-of-life domains were improved following the intervention, including physical (P = .002), emotional (P < .001), and role functioning (P = .018), fatigue (P = .030), and appetite loss (P = .005). CONCLUSION: A 3-month exercise program based on a patient-preferred delivery mode is feasible in patients with metastatic cancer and may improve physical function and quality of life. TRIAL REGISTRATION: NCT04226508.


Assuntos
Terapia por Exercício , Estudos de Viabilidade , Neoplasias , Qualidade de Vida , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exercício Físico/fisiologia , Terapia por Exercício/métodos , Força Muscular/fisiologia , Metástase Neoplásica , Preferência do Paciente/estatística & dados numéricos
18.
Thorax ; 79(4): 340-348, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38129116

RESUMO

OBJECTIVE: The objective of this study is to compare the effectiveness of lower limb low-load blood flow restriction training (LL-BFRT) with high-load strength training (HL-ST) as part of an outpatient pulmonary rehabilitation programme on leg strength in patients with chronic obstructive pulmonary disease (COPD). METHODS: Participants were randomised to LL-BFRT or HL-ST (24 sessions). LL-BFRT was done at 30% 1-repetition maximum (1-RM) with 70% arterial occlusion pressure. HL-ST was done at 70% 1-RM. Primary outcome was isometric strength of knee extensors and flexors. Secondary outcomes were 1-RM, functional exercise capacity, physical activity, symptom burden and health-related quality of life. Perceptions of dyspnoea and leg fatigue were recorded after every exercise. We compared groups with t-tests. RESULTS: We included 30 participants (13 women, 17 men, 64 (9) years, forced expiratory volume in 1 s 47 (18)% pred.), 24 completed the study. Isometric knee extensor strength improved to a clinically relevant degree in both legs in both groups (LL-BFRT: right leg 9 (20) Nm, left leg 10 (18) Nm; HL-ST: right leg 15 (26) Nm, left leg 16 (30) Nm, data are mean (SD)), without statistically significant or clinically relevant between-group differences (right leg mean difference= -6.4, 95% CI= -13.20 to 25.92 Nm, left leg mean difference= -5.6, 95% CI= -15.44 to 26.55 Nm). 1 min sit-to-stand test performance improved to a clinically relevant degree only in the LL-BFRT group (4 (4) vs 1 (5) repetitions). Interestingly, physical activity improved to a clinically relevant degree only in the LL-BFRT group (1506 (2441) vs -182 (1971) steps/day). LL-BFRT lowered perceived in-exercise dyspnoea and increased leg fatigue compared with HL-ST in the initial 12 trainings. CONCLUSION: In patients with stable COPD undergoing outpatient pulmonary rehabilitation, LL-BFRT was not superior to HL-ST in improving leg strength. LL-BFRT led to similar strength gains as HL-ST while reducing perceptions of dyspnoea in the initial training phase. TRIAL REGISTRATION NUMBER: NCT04151771.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Treinamento Resistido , Masculino , Humanos , Feminino , Projetos Piloto , Qualidade de Vida , Terapia de Restrição de Fluxo Sanguíneo , Método Simples-Cego , Doença Pulmonar Obstrutiva Crônica/reabilitação , Dispneia/etiologia , Fadiga , Força Muscular
19.
Thorax ; 79(8): 711-717, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38914469

RESUMO

RATIONALE: Endoscopic lung volume reduction improves lung function, quality of life and exercise capacity in severe emphysema patients. However, its effect on the diaphragm function is not well understood. We hypothesised that endoscopic lung volume reduction increases its strength by modifying its shape. OBJECTIVES: To investigate changes in both diaphragm shape and strength induced by the insertion of endobronchial valves. METHODS: In 19 patients, both the diaphragm shape and strength were investigated respectively by 3D Slicer software applied on CT scans acquired at functional residual capacity and by transdiaphragmatic pressure measurements by bilateral magnetic stimulation of the phrenic nerves before and 3 months after unilateral valves insertion. MEASUREMENTS AND MAIN RESULTS: After lung volume reduction (median (IQR), 434 mL (-597 to -156], p<0.0001), diaphragm strength increased (transdiaphragmatic pressure: 3 cmH2O (2.3 to 4.2), p<0.0001). On the treated side, this increase was associated with an increase in the coronal (16 mm (13 to 24), p<0.0001) and sagittal (26 mm (21 to 30), p<0.0001) lengths as well as in the area of the zone of apposition (62 cm2 (3 to 100), p<0.0001) with a decrease in the coronal (8 mm (-12 to -4), p<0.0001) and sagittal (9 mm (-18 to -2), p=0.0029) radii of curvature. CONCLUSIONS: Endoscopic lung volume reduction modifies the diaphragm shape by increasing its length and its zone of apposition and by decreasing its radius of curvature on the treated side, resulting in an increase in its strength. TRIAL REGISTRATION NUMBER: NCT05799352.


Assuntos
Diafragma , Pneumonectomia , Enfisema Pulmonar , Tomografia Computadorizada por Raios X , Humanos , Diafragma/diagnóstico por imagem , Masculino , Pneumonectomia/métodos , Feminino , Pessoa de Meia-Idade , Idoso , Enfisema Pulmonar/cirurgia , Enfisema Pulmonar/fisiopatologia , Enfisema Pulmonar/diagnóstico por imagem , Broncoscopia/métodos , Força Muscular/fisiologia , Capacidade Residual Funcional/fisiologia
20.
Breast Cancer Res Treat ; 207(3): 569-578, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38851662

RESUMO

BACKGROUND: An increasing number of women are choosing mastectomy and subpectoral implant (SI) breast reconstruction over breast-conserving therapy (BCT). It is unclear to what extent these procedures differ in their effect on the pectoralis major (PM). The purpose of this study was to assess the impact of choosing BCT or SI breast reconstruction on PM function. METHODS: Ultrasound shear wave elastography images were acquired from the PM fiber regions and surface electromyography obtained activity from six shoulder muscles, while 14 BCT participants, 14 SI participants, and 14 age-matched controls remained at rest or generated submaximal shoulder torques. RESULTS: BCT and SI participants were significantly weaker in shoulder adduction, while BCT participants were also weaker in internal and external rotation (all p ≤ 0.003). PM function was altered following either BCT or SI. In all treatment groups, the clavicular fiber region contributed primarily to flexion, and the sternocostal primarily contributed to adduction. However, healthy participants utilized the clavicular region more during adduction and the sternocostal region more during flexion when compared to BCT or SI participants (all p ≤ 0.049). The still intact clavicular region increased its contributions to flexion torques in SI participants compared to controls (p = 0.016). Finally, BCT and SI participants compensated for changes in PM function using synergistic shoulder musculature. CONCLUSION: Both BCT and SI breast reconstruction result in significant long-term upper extremity strength deficits. Our results suggest changes to the underlying function of the PM and the adoption of unique but inadequate neuromuscular compensation strategies drive these deficits.


Assuntos
Neoplasias da Mama , Músculos Peitorais , Humanos , Feminino , Músculos Peitorais/cirurgia , Pessoa de Meia-Idade , Neoplasias da Mama/cirurgia , Adulto , Mastectomia Segmentar/métodos , Eletromiografia , Mastectomia/métodos , Mastectomia/efeitos adversos , Técnicas de Imagem por Elasticidade/métodos , Mamoplastia/métodos , Implantes de Mama , Força Muscular , Estudos de Casos e Controles , Ombro/cirurgia , Amplitude de Movimento Articular
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