Role of anatomical location, cellular phenotype and perfusion of adipose tissue in intermediary metabolism: A narrative review

It is well-established that adipose tissue accumulation is associated with insulin resistance through multiple mechanisms. One major metabolic link is the classical Randle cycle: enhanced release of free fatty acids (FFA) from hydrolysis of adipose tissue triglycerides impedes insulin-mediated glucose uptake in muscle tissues. Less well studied are the different routes of this communication. First, white adipose tissue depots may be regionally distant from muscle (i.e., gluteal fat and diaphragm muscle) or contiguous to muscle but separated by a fascia (Scarpa’s fascia in the abdomen, fascia lata in the thigh). In this case, released FFA outflow through the venous drainage and merge into arterial plasma to be transported to muscle tissues. Next, cytosolic triglycerides can directly, i.e., within the cell, provide FFA to myocytes (but also pancreatic ß-cells, renal tubular cells, etc.). Finally, adipocyte layers or lumps may be adjacent to, but not anatomically segregated, from muscle, as is typically the case for epicardial fat and cardiomyocytes. As regulation of these three main delivery paths is different, their separate contribution to substrate competition at the whole-body level is uncertain. Another important link between fat and muscle is vascular. In the resting state, blood flow is generally higher in adipose tissue than in muscle. In the insulinized state, fat blood flow is directly related to whole-body insulin resistance whereas muscle blood flow is not; consequently, fractional (i.e., flow-adjusted) glucose uptake is stimulated in muscle but not fat. Thus, reduced blood supply is a major factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect.

The role of diaphragmatic ultrasound as a predictor of successful extubation from mechanical ventilation in respiratory intensive care unit

Background The diaphragm muscle whose dysfunction may be very common in patients undergoing mechanical ventilation (Ferrari G, De Filippi G, Elia F, Panero F, Volpicelli G, Aprà F. Crit Ultrasound J 6:8, 2014). Aim: To evaluate real-time ultrasound in the evaluation of diaphragmatic thickening, thickening fraction, and/or excursion to predict extubation outcomes. We aimed to compare these parameters with other traditional weaning measures is a fundamental. Results Out of 80 included patients, 20 (25%) have failed extubation. Diaphragmatic thickening (DT), thickening fraction (DTF), and/or excursion (DE) were significantly higher in the successful group compared to those who failed extubation (p < 0.05). Cutoff values of diaphragmatic measures associated with successful extubation (during tidal breathing) were ≥ 17 mm for DE; ≥ 2.1 cm for DT inspiration; ≥ 15.5 mm for DT expiration, functional residual capacity (FRC); and ≥ 32.82% for DTF %, giving 68%, 95%, 62%, and 90% sensitivity, respectively, and 65%, 100%, 100%, and 75% specificity, respectively. Cutoff values of diaphragmatic parameters associated with successful extubation (during deep breathing) were > 28.5 mm DT Insp, total lung capacity (TLC); >22.5mm DT Exp (RV); >37 DTF %; and > 31 mm DE, giving 100%, 73%, 97%, and 75% sensitivity and 65%, 75%, 100%, and 55% specificity, respectively. Rapid shallow breathing index (RSBI) had 47% sensitivity but 90% specificity. Conclusion Ultrasound evaluation of diaphragmatic parameters could be a good predictor of weaning in patients who passed the T-tube.

The Main Role of Diaphragm Muscle as a Mechanism of Hypopressive Abdominal Gymnastics to Improve Non-Specific Chronic Low Back Pain: A Randomized Controlled Trial

Background: Chronic low back pain (LBP) has been stated as one of the main health concerns in the XXI century due to its high incidence. Objective: The objective of this study was to determine the effects of an 8-week program of hypopressive abdominal gymnastics (HAG) on inspiratory muscle strength, diaphragm thickness, disability and pain in patients suffering from non-specific chronic LBP. Methods: A total of 40 patients with chronic LBP were randomly divided into two groups. The experimental group carried out an 8-week supervised program of HAG (two sessions/week), whereas the control group did not receive any treatment. Outcomes were measured before and after the intervention, comprising diaphragm thickness during relaxed respiratory activity, maximal inspiratory pressure (PImax), pain intensity (NRS), pressure pain threshold and responses to four questionnaires: Physical Activity Questionnaire (PAQ), Roland–Morris Disability Questionnaire (RMQ), Central Sensitization Inventory (CSI) and Tampa Scale of Kinesiophobia-11 Items (TSK-11). Results: Statistically significant differences (p < 0.05) were observed for greater thickness of the left and right hemi-diaphragms at inspiration, as well as higher PImax and decreased NRS, CSI and RMQ scores in the intervention group. After treatment, the increases in the thickness of the left and right hemi-diaphragms at inspiration and PImax, as well as the decrease in the NRS and RMQ scores, were only predicted by the proposed intervention (R2 = 0.118–0.552). Conclusions: An 8-week HAG intervention seemed to show beneficial effects and predicted an increase in diaphragm thickness and strength during inspiration, as well as a reduction in pain intensity, central sensitization and disability, in patients suffering from chronic non-specific LBP with respect to non-intervention.

Fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm

The diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, Congenital Diaphragmatic Hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors or potentially the phrenic nerve have not been explicitly tested. Using conditional mutagenesis and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue, are the source of HGF critical for diaphragm muscularization and phrenic nerve primary branching. HGF not only is required for recruitment of muscle progenitors to the diaphragm, but is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Thus, the connective tissue fibroblasts and HGF coordinately regulate diaphragm muscularization and innervation. Defects in PPF-derived HGF result in muscleless regions that are susceptible to CDH.Summary StatementFibroblast-derived HGF signals to Met+ muscle progenitors and nerve to control the expansion of diaphragm muscle and primary branching of phrenic nerve axons - structures critical for breathing in mammals.

Mitochondrial Fragmentation and Dysfunction in Type IIx/IIb Diaphragm Muscle Fibers in 24-Month Old Fischer 344 Rats

Sarcopenia is characterized by muscle fiber atrophy and weakness, which may be associated with mitochondrial fragmentation and dysfunction. Mitochondrial remodeling and biogenesis in muscle fibers occurs in response to exercise and increased muscle activity. However, the adaptability mitochondria may decrease with age. The diaphragm muscle (DIAm) sustains breathing, via recruitment of fatigue-resistant type I and IIa fibers. More fatigable, type IIx/IIb DIAm fibers are infrequently recruited during airway protective and expulsive behaviors. DIAm sarcopenia is restricted to the atrophy of type IIx/IIb fibers, which impairs higher force airway protective and expulsive behaviors. The aerobic capacity to generate ATP within muscle fibers depends on the volume and intrinsic respiratory capacity of mitochondria. In the present study, mitochondria in type-identified DIAm fibers were labeled using MitoTracker Green and imaged in 3-D using confocal microscopy. Mitochondrial volume density was higher in type I and IIa DIAm fibers compared with type IIx/IIb fibers. Mitochondrial volume density did not change with age in type I and IIa fibers but was reduced in type IIx/IIb fibers in 24-month rats. Furthermore, mitochondria were more fragmented in type IIx/IIb compared with type I and IIa fibers, and worsened in 24-month rats. The maximum respiratory capacity of mitochondria in DIAm fibers was determined using a quantitative histochemical technique to measure the maximum velocity of the succinate dehydrogenase reaction (SDHmax). SDHmax per fiber volume was higher in type I and IIa DIAm fibers and did not change with age. In contrast, SDHmax per fiber volume decreased with age in type IIx/IIb DIAm fibers. There were two distinct clusters for SDHmax per fiber volume and mitochondrial volume density, one comprising type I and IIa fibers and the second comprising type IIx/IIb fibers. The separation of these clusters increased with aging. There was also a clear relation between SDHmax per mitochondrial volume and the extent of mitochondrial fragmentation. The results show that DIAm sarcopenia is restricted to type IIx/IIb DIAm fibers and related to reduced mitochondrial volume, mitochondrial fragmentation and reduced SDHmax per fiber volume.

MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases

Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µM/kg, i.p.) and atropine (50 µM/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD50 dose of paraoxon.