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The Journal of Physiology Oct 2023Despite profound diaphragm weakness, peak inspiratory pressure-generating capacity is preserved in young mdx mice revealing adequate compensation by extra-diaphragmatic...
Despite profound diaphragm weakness, peak inspiratory pressure-generating capacity is preserved in young mdx mice revealing adequate compensation by extra-diaphragmatic muscles of breathing in early dystrophic disease. We hypothesised that loss of compensation gives rise to respiratory system compromise in advanced dystrophic disease. Studies were performed in male wild-type (n = 196) and dystrophin-deficient mdx mice (n = 188) at 1, 4, 8, 12 and 16 months of age. In anaesthetised mice, inspiratory pressure and obligatory and accessory respiratory EMG activities were recorded during baseline and sustained tracheal occlusion for up to 30-40 s to evoke peak system activation to task failure. Obligatory inspiratory EMG activities were lower in mdx mice across the ventilatory range to peak activity, emerging in early dystrophic disease. Early compensation protecting peak inspiratory pressure-generating capacity in mdx mice, which appears to relate to transforming growth factor-β1-dependent fibrotic remodelling of the diaphragm and preserved accessory muscle function, was lost at 12 and 16 months of age. Denervation and surgical lesion of muscles of breathing in 4-month-old mice revealed a greater dependency on diaphragm for peak inspiratory performance in wild-type mice, whereas mdx mice were heavily dependent upon accessory muscles (including abdominal muscles) for peak performance. Accessory EMG activities were generally preserved or enhanced in young mdx mice, but peak EMG activities were lower than wild-type by 12 months of age. In general, ventilation was reasonably well protected in mdx mice until 16 months of age. Despite the early emergence of impairments in the principal obligatory muscles of breathing, peak inspiratory performance is compensated in early dystrophic disease due to diaphragm remodelling and facilitated contribution by accessory muscles of breathing. Loss of compensation afforded by accessory muscles underpins the emergence of respiratory system morbidity in advanced dystrophic disease. KEY POINTS: Despite diaphragm weakness, peak inspiratory performance is preserved in young dystrophin-deficient mdx mice revealing adequate compensation by extra-diaphragmatic muscles. Peak obligatory muscle (diaphragm, external intercostal, and parasternal intercostal) EMG activities are lower in mdx mice, emerging early in dystrophic disease, before the temporal decline in peak performance. Peak EMG activities of some accessory muscles are lower, whereas others are preserved. There is greater recruitment of the trapezius muscle in mdx mice during peak system activation. In phrenicotomised mice with confirmed diaphragm paralysis, there is a greater contribution made by extra-diaphragmatic muscles to peak inspiratory pressure in mdx compared with wild-type mice. Surgical lesion of accessory (including abdominal) muscles adversely affects peak pressure generation in mdx mice. Diaphragm remodelling leading to stiffening provides a mechanical advantage to peak pressure generation via the facilitated action of extra-diaphragmatic muscles in early dystrophic disease. Peak accessory EMG activities are lower in 12-month-old mdx compared to wild-type mice. Peak inspiratory pressure declines in mdx mice with advanced disease. We conclude that compensation afforded by accessory muscles of breathing declines in advanced dystrophic disease precipitating the emergence of respiratory system dysfunction.
Topics: Male; Mice; Animals; Mice, Inbred mdx; Muscular Dystrophy, Duchenne; Dystrophin; Diaphragm; Respiratory System; Respiration Disorders; Muscle Weakness; Respiratory Muscles
PubMed: 37688347
DOI: 10.1113/JP285203 -
European Journal of Pediatrics Jul 2023Skeletal muscle atrophy is known to be a marker for nutritional deficiency. The diaphragm is both a skeletal muscle and a respiratory muscle. There is not enough data in...
Skeletal muscle atrophy is known to be a marker for nutritional deficiency. The diaphragm is both a skeletal muscle and a respiratory muscle. There is not enough data in the literature about the change in diaphragm thickness (DT) in children with malnutrition. We think that malnutrition may have negative effects on diaphragm thickness. Therefore, in this study, we aimed to compare the diaphragm thicknesses of pediatric patients with primary malnutrition and a healthy control group. The DT of pediatric patients diagnosed with primary malnutrition by a pediatric gastroenterologist was prospectively evaluated by a radiology specialist by ultrasonography (USG). The obtained data were statistically compared with the data of the healthy control group. There was no statistically significant difference between the groups in terms of age and gender (p = 0.244, p = 0.494). We found that right and left diaphragm thicknesses were significantly thinner in the malnourished group than in the healthy control group (p = 0.001, p = 0.009, respectively). We found that right and left diaphragm thicknesses were thinner in those with moderate and severe malnutrition compared to the normal group (p < 0.001, p = 0.003, respectively). We found a significant weak positive correlation between weight and height Z score and right and left diaphragm thickness (respectively, r: 0.297, p < 0.001; r: 0.301, p < 0.001). Conclusion: Malnutrition is a disease that affects all systems. Our study shows that the DT is thinner in patients with malnutrition. What is Known: •Malnutrition causes skeletal muscle atrophy. What is New: •Diaphragm muscle thickness decreases in malnutrition. •There is a significant positive correlation between diaphragm muscle thickness and height, weight and BMI z scores.
Topics: Humans; Child; Diaphragm; Malnutrition; Muscle, Skeletal; Muscular Atrophy; Ultrasonography
PubMed: 37178359
DOI: 10.1007/s00431-023-05024-x -
Acta Biomaterialia Sep 2023Duchenne muscular dystrophy (DMD) causes patients to suffer from ambulatory disability and cardiorespiratory failure, the latter of which leads to premature death. Due...
Duchenne muscular dystrophy (DMD) causes patients to suffer from ambulatory disability and cardiorespiratory failure, the latter of which leads to premature death. Due to its role in respiration, the diaphragm is an important muscle for study. A common method for evaluating diaphragm function is ex vivo force testing, which only allows for an end point measurement. In contrast, ultrasound shear wave elastography imaging (US-SWEI) can assess diaphragm function over time; however, US-SWEI studies in dystrophic patients to date have focused on the limbs without preclinical studies. In this work, we used US-SWEI to estimate the shear wave speed (SWS) in diaphragm muscles of healthy (WT) mice, mdx mice, and mdx mice haploinsufficient for utrophin (mdx-utr) at 6 and 12 months of age. Diaphragms were then subjected to ex vivo force testing and histological analysis at 12 months of age. Between 6 and 12 months, a 23.8% increase in SWS was observed in WT mice and a 27.8% increase in mdx mice, although no significant difference was found in mdx-utr mice. Specific force generated by mdx-utr diaphragms was lower than that of WT diaphragms following twitch stimulus. A strong correlation between SWS and collagen deposition was observed, as well as between SWS and muscle fiber size. Together, these data demonstrate the ability of US-SWEI to evaluate dystrophic diaphragm functionality over time and predict the biochemical and morphological make-up of the diaphragm. Additionally, our results highlight the advantage of US-SWEI over ex vivo testing by obtaining longitudinal measurements in the same subject. STATEMENT OF SIGNIFICANCE: In DMD patients, muscles experience cycles of regeneration and degeneration that contribute to chronic inflammation and muscle weakness. This pathology only worsens with time and leads to muscle wasting, including in respiratory and cardiac muscles. Because respiratory failure is a major contributor to premature death in DMD patients, the diaphragm muscle is an important muscle to evaluate and treat over time. Currently, diaphragm function is assessed using ex vivo force testing, a technique that only allows measurement at sacrifice. In contrast, ultrasonography, particularly shear wave elasticity imaging (USSWEI), is a promising tool for longitudinal assessment; however, most US-SWEI in DMD patients aimed for limb muscles only with the absence of preclinical studies. This work broadens the applications of US-SWE imaging by demonstrating its ability to track properties and function of dystrophic diaphragm muscles longitudinally in multiple dystrophic mouse models.
Topics: Mice; Animals; Mice, Inbred mdx; Diaphragm; Mice, Inbred C57BL; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Elasticity; Disease Models, Animal
PubMed: 37453552
DOI: 10.1016/j.actbio.2023.07.009 -
Experimental Neurology Aug 2024Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately,...
Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately, clinical use of DOX is limited due to adverse off-target effects resulting in fatigue, respiratory muscle weakness and dyspnea. The diaphragm is the primary muscle of inspiration and respiratory insufficiency is likely the result of both muscle weakness and neural impairment. However, the contribution of neuropathology to DOX-induced respiratory muscle dysfunction is unclear. We hypothesized that diaphragm weakness following acute DOX exposure is associated with neurotoxicity and that exercise preconditioning is sufficient to improve diaphragm muscle contractility by maintaining neuromuscular integrity. Adult female Sprague-Dawley rats were randomized into four experimental groups: 1) sedentary-saline, 2) sedentary-DOX, 3) exercise-saline or 4) exercise-DOX. Endurance exercise preconditioning consisted of treadmill running for 1 h/day at 30 m/min for 10 days. Twenty-four hours after the last bout of exercise, animals were treated with DOX (20 mg/kg, I.P.) or saline (equal volume). Our results demonstrate that 48-h following DOX administration diaphragm muscle specific force is reduced in sedentary-DOX rats in response to both phrenic nerve and direct diaphragm stimulation. Importantly, endurance exercise preconditioning in DOX-treated rats attenuated the decrease in diaphragm contractile function, reduced neuromuscular transmission failure and altered phrenic nerve morphology. These changes were associated with an exercise-induced reduction in circulating biomarkers of inflammation, nerve injury and reformation. Therefore, the results are consistent with exercise preconditioning as an effective way of reducing respiratory impairment via preservation of phrenic-diaphragm neuromuscular conduction.
Topics: Animals; Diaphragm; Rats, Sprague-Dawley; Doxorubicin; Female; Rats; Physical Conditioning, Animal; Antibiotics, Antineoplastic; Synaptic Transmission; Phrenic Nerve; Muscle Contraction; Neuromuscular Junction
PubMed: 38782352
DOI: 10.1016/j.expneurol.2024.114818 -
Ultrasound in Medicine & Biology Jul 2023We investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine...
OBJECTIVE
We investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine the pattern of muscle compromise in patients with SMA and the potential role of ultrasound to evaluate disease progression.
METHODS
We examined muscles (biceps brachii, rectus femoris, diaphragm, intercostals and thoracic multifidus) of 41 patients with SMA (types 1 to 4) and 46 healthy age- and sex-matched control individuals using B-mode ultrasound for gray-scale analysis (GSA), area (biceps brachii and rectus femoris) and diaphragm thickening ratio. Functional scales were applied to patients only. We analyzed ultrasound abnormalities in specific clinical subtypes and correlated findings with functional status.
RESULTS
Compared with controls, patients had reduced muscle area and increased mean GSA for all muscles (p < 0.001), with an established correlation between the increase in GSA and the severity of SMA for biceps brachii, rectus femoris and intercostals (p = 0.03, 0.01 and 0.004 respectively) when using the Hammersmith Functional Motor Scale Expanded. Diaphragm thickening ratio was normal in the majority of patients, and intercostal muscles had higher GSA than diaphragm in relation to the controls.
CONCLUSION
Ultrasound is useful for quantifying muscular changes in SMA and correlates with functional status. Diaphragm thickening ratio can be normal even with severe compromise of respiratory muscles in quantitative analysis, and intercostal muscles were more affected than diaphragm.
Topics: Humans; Muscular Atrophy, Spinal; Muscle, Skeletal; Ultrasonography; Diaphragm; Intercostal Muscles
PubMed: 37037685
DOI: 10.1016/j.ultrasmedbio.2023.02.021 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue Nov 2023Mechanical ventilation has, since its introduction into clinical practice, undergone a major evolution from controlled ventilation to diverse modes of assisted... (Review)
Review
Mechanical ventilation has, since its introduction into clinical practice, undergone a major evolution from controlled ventilation to diverse modes of assisted ventilation. Conventional mechanical ventilators depend on flow sensors and pneumatic pressure and controllers to complete the respiratory cycle. Neurally adjusted ventilatory assist (NAVA) is a new form of assisted ventilation in recent years, which monitors the electrical activity of the diaphragm (EAdi) to provide an appropriately level of pressure support. And EAdi is the best available signal to sense central respiratory drive and trigger ventilatory assist. Unlike other ventilation modes, NAVA breathing instructions come from the center. Therefore, NAVA have the synchronous nature of the breaths and the patient-adjusted nature of the support. Compared with traditional ventilation mode, NAVA can efficiently unload respiratory muscles, relieve the risk of ventilator-induced lung injury (VILI), improve patient-ventilator coordination, enhance gas exchange, increase the success rate of weaning, etc. This article reviews the research progress of NAVA in order to provide theoretical guidance for clinical applications.
Topics: Humans; Interactive Ventilatory Support; Respiration, Artificial; Positive-Pressure Respiration; Diaphragm; Respiratory Muscles
PubMed: 37987137
DOI: 10.3760/cma.j.cn121430-20230222-00101 -
Journal of Equine Veterinary Science Jul 2024Ultrasonographic imaging of the diaphragm is a non-invasive alternative for respiratory function evaluation in horses. This study aimed to measure diaphragm thickness,...
Ultrasonographic imaging of the diaphragm is a non-invasive alternative for respiratory function evaluation in horses. This study aimed to measure diaphragm thickness, thickening (change in thickness with contraction) and thickening fraction in healthy adult horses during tidal breathing and forced vital capacity. Correlation between body weight (≤400 kg and >400 kg) and diaphragm thickness was investigated. To that purpose, 20 adult horses, weight 409±50 kg, height 1.47±0.05 m, and age 16±6 years were included in the study. Diaphragm thickness was measured at end-inspiration and end-expiration using B-mode and M-mode. The transducer was placed in the 10th, 11th and 12th intercostal spaces of both hemithoraces. Measurements obtained at end inspiration using M-mode during forced vital capacity were greater than for tidal breathing for diaphragm thickness (P=0.006), diaphragm thickening (P<0.001) and thickening fraction (P<0.001). The same was found for thickening (P<0.001) and thickening fraction (P<0.001). Diaphragm thickness at end-inspiration was greater in horses weighing >400kg than those ≤400kg at the inspiration (0.93±0.2 cm and 0.74±0 0.02 cm, P<0.001) and at the end of expiration (0.77±0.02 cm and 0.63±0, 02 cm, P<0.001). There was no difference in thickening fraction between horses weighing ≤400kg and >400kg (tidal breathing: 18±2 % and 16±2 %, P=0.609; forced vital capacity: 39±6 % and 31±5 %, P=0.301). Diaphragm assessment in horses is possible using both B-mode and M-mode. Breathing workload has a positive correlation between breathing workload and diaphragm contraction. Due to the relationship demonstrated between diaphragm thickness and weight, it is recommended that diaphragm thickening fraction is used to compare diaphragm measurements between horses.
Topics: Horses; Animals; Diaphragm; Ultrasonography; Male; Female
PubMed: 38763366
DOI: 10.1016/j.jevs.2024.105100 -
Acta Physiologica (Oxford, England) May 2024Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs...
AIM
Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD.
METHODS
Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined.
RESULTS
CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region.
CONCLUSION
JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.
Topics: Animals; Diaphragm; Pyrimidines; Nitriles; Rats; Respiration, Artificial; Male; Pyrazoles; Rats, Sprague-Dawley
PubMed: 38551103
DOI: 10.1111/apha.14128 -
BMC Pulmonary Medicine Sep 2023Diaphragmatic dysfunction is known to be associated with difficulties weaning from invasive mechanical ventilation and is related to worse patient outcomes yet our... (Observational Study)
Observational Study
BACKGROUND
Diaphragmatic dysfunction is known to be associated with difficulties weaning from invasive mechanical ventilation and is related to worse patient outcomes yet our understanding of how to prevent diaphragmatic dysfunction remains incomplete. We examined potentially modifiable risk factors for diaphragmatic dysfunction and attempted to estimate benefits attributable to altering these modifiable risk factors.
METHODS
This prospective multicenter observational study was undertaken in the general ICUs of two tertiary care teaching hospitals. Critically ill adults expected to receive invasive mechanical ventilation for at least 48 h were enrolled. Diaphragm function was assessed by ultrasound each study day, with dysfunction defined as thickening fraction less than 20%.
RESULTS
From January to December 2019, 856 patients were screened and 126 patients were enrolled. Overall, 40.5% (51/126) of patients experienced diaphragmatic dysfunction during invasive mechanical ventilation. Patients with diaphragmatic dysfunction were more likely to develop ventilator associated pneumonia (risk difference [RD] + 12.9%, 95% Confidence Interval [CI] 1.4 to 24.4%, P = 0.028), were more likely to experience extubation failure (RD + 8.5%, 95% CI 0.4 to 16.6%, P = 0.039) and required a longer duration of invasive mechanical ventilation (RD + 1.3 days, 95% CI 0.1 to 2.5 days, P = 0.035). They also required a longer hospital stay (RD + 1.2 days, 95% CI 0.04 to 2.4 days, P = 0.041) and were more likely to die before hospital discharge (RD + 18.1%, 95% CI 3.7 to 32.5%, P = 0.014). Multivariable analysis considered the impact of age, sex, pre-existing nutritional status, caloric intake, amino acid intake, acute disease severity, modes of mechanical ventilation, measures of respiratory status, sedation, pain control and baseline diaphragm thickness. Only SOFA score (P = 0.008) and early amino acid intake (P = 0.001) remained significant independent risk factors for the onset of diaphragmatic dysfunction. Causal path modeling suggested early amino acid intake may significantly reduce diaphragmatic dysfunction (RRR 29%, 95% CI 10% to 48%, P = 0.003) and may also reduce mortality (RRR 49%, 95% CI 25% to 73%, P < 0.0001).
CONCLUSIONS
Amino acid intake during the first 24 h of ICU stay may represent an important, modifiable risk factor for diaphragmatic dysfunction and may have a direct causal effect on mortality. We recommend additional research on this topic.
Topics: Adult; Humans; Diaphragm; Prospective Studies; Ventilators, Mechanical; Risk Factors; Amino Acids
PubMed: 37700263
DOI: 10.1186/s12890-023-02633-y