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The diaphragm is the main skeletal muscle responsible for inspiration and is susceptible to age-associated decline in function and morphology. Satellite cells in diaphragm fuse into unperturbed muscle fibers throughout life, yet their role in adaptations to hypoxia in diaphragm is unknown. Given their continual fusion, we hypothesize that satellite cell depletion will negatively impact adaptations to hypoxia in the diaphragm, particularly with aging. We used the Pax7

Many patients with anterior cruciate ligament (ACL) injuries have persistent quadriceps muscle atrophy, even after considerable time in rehabilitation. Understanding the factors that regulate muscle mass, and the time course of atrophic events, is important for identifying therapeutic interventions. With a noninvasive animal model of ACL injury, a longitudinal study was performed to elucidate key parameters underlying quadriceps muscle atrophy. Male Long-Evans rats were euthanized at 6, 12, 24, or 48 h or 1, 2, or 4 wk after ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle size was determined by wet weight and fiber cross-sectional area (CSA). Evidence of disrupted neuromuscular communication was assessed via the expression of neural cell adhesion molecule (NCAM) and genes associated with denervation and neuromuscular junction instability. Abundance of muscle RING-finger protein-1 (MuRF-1), muscle atrophy F-box (MAFbx), and 45 s pre-rRNA along with 20S proteasome activity were determined to investigate mechanisms related to muscle atrophy. Finally, muscle damage-related parameters were assessed by measuring IgG permeability, centronucleation, CD68 mRNA, and satellite cell abundance. When compared with controls, we observed a greater percentage of NCAM-positive fibers at 6 h postinjury, followed by higher MAFbx abundance 48 h postinjury, and higher 20S proteasome activity at 1 wk postinjury. A loss of muscle wet weight, smaller fiber CSA, and the elevated expression of run-related transcription factor 1 (Runx1) were also observed at the 1 wk postinjury timepoint relative to controls. There also were no differences observed in any damage markers. These results indicate that alterations in neuromuscular communication precede the upregulation of atrophic factors that regulate quadriceps muscle mass early after noninvasive ACL injury. NEW & NOTEWORTHY A novel preclinical model of ACL injury was used to establish that acute disruptions in neuromuscular communication precede atrophic events. These data help to establish the time course of muscle atrophy after ACL injury, suggesting that clinical care may benefit from the application of acute neurogenic interventions and early gait reloading strategies.

The skeletal muscle research field generally accepts that nuclei in skeletal muscle fibers (i.e., myonuclei) are post-mitotic and unable to proliferate. Because our deuterium oxide (D2O) labeling studies showed DNA synthesis in skeletal muscle tissue, we hypothesized that resident myonuclei can replicatein vivo. To test this hypothesis, we used a mouse model that temporally labeled myonuclei with GFP followed by D2O labeling during normal cage activity, functional overload, and with satellite cell ablation. During normal cage activity, we observed deuterium enrichment into myonuclear DNA in 7 out of 7 plantaris (PLA), 6 out of 6 tibialis anterior (TA), 5 out of 7 gastrocnemius (GAST) and 7 out of 7 quadriceps (QUAD). The average fractional synthesis rates (FSR) of DNA in myonuclei were: 0.0202 ± 0.0093 in PLA, 0.0239 ± 0.0040 in TA, 0.0076 ± 0. 0058 in GAST, and 0.0138 ± 0.0039 in QUAD, while there was no replication in myonuclei from EDL. These FSR values were largely reproduced in the overload and satellite cell ablation conditions although there were higher synthesis rates in the overloaded PLA muscle. We further provided evidence that myonuclear replication is through endoreplication that results in polyploidy. These novel findings contradict the dogma that skeletal muscle nuclei are post-mitotic and open potential avenues to harness the intrinsic replicative ability of myonuclei for muscle maintenance and growth.Graphical Abstract

The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14 days of hindlimb suspension, followed by 7 days of recovery with (RE + M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross-sectional area were observed between RE and RE + M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin−/laminin+ fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.

Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.

Muscle atrophy is among the most common conditions during sickness, injury, aging and after orthopedic surgeries, and is associated with poor health outcomes. As such, it is important to understand the molecular machinery responsible for the control of muscle mass and function for development of therapeutic targets and strategies to combat muscle atrophy. We have identified the cold shock RNA binding protein, RNA-binding motif protein 3 (RBM3) as a critical regulatory node in the control of skeletal muscle mass and herein, we review our current knowledge of its actions in skeletal muscle. We also cover future directions of research and how this knowledge may translate into therapeutic interventions.

Massage is a viable mechanotherapy to improve protein turnover during disuse atrophy and improve muscle regrowth during recovery from disuse atrophy in adult muscle. Therefore, we investigated whether massage can cause beneficial adaptations in skeletal muscle from aged rats during normal weight-bearing (WB) conditions, hindlimb suspension (HS), or reloading (RE) following HS. Aged (30 months) male Fischer 344/Brown Norway rats were divided into two experiments: (1) WB for 7 days (WB, n = 8), WB with massage (WBM, n = 8), HS for 7 days (HS7, n = 8), or HS with massage (HSM, n = 8), and (2) WB for 14 days (WB14, n = 8), HS for 14 days (HS14, n = 8), reloading (RE, n = 10), or reloading with massage (REM, n = 10) for 7 days following HS. Deuterium oxide (D(2)O) labeling was used to assess dynamic protein and ribosome turnover in each group and anabolic signaling pathways were assessed. Massage did have an anabolic benefit during RE or WB. In contrast, massage during HS enhanced myofibrillar protein turnover in both the massaged limb and contralateral non-massaged limb compared with HS, but this did not prevent muscle loss. Overall, the data demonstrate that massage is not an effective mechanotherapy for prevention of atrophy during muscle disuse or recovery of muscle mass during reloading in aged rats. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00215-y) contains supplementary material, which is available to authorized users.

To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.

Objective Previous studies have demonstrated that muscle ultrasound (US) can be reliably performed at the patient bedside by novice assessors with minimal training. The primary objective of this study was to determine the interrater reliability of muscle US image acquisition by physical therapists and physical therapist students. Secondarily, this study was designed to elucidate the process for training physical therapists to perform peripheral skeletal muscle US. Methods This was a cross-sectional observational study. Four novices and 1 expert participated in the study. Novice sonographers engaged in a structured training program prior to implementation. US images were obtained on the biceps brachii, quadriceps femoris, and tibialis anterior muscles in 3 groups: patients in the intensive care unit, patients on the hospital ward, and participants in the outpatient gym who were healthy. Reliability of image acquisition was analyzed compared with the expert sonographer. Results Intraclass correlation coefficient values ranged from 0.76 to 0.97 with an average for all raters and all muscles of 0.903, indicating excellent reliability of image acquisition. In general, the experienced physical therapist had higher or similar intraclass correlation coefficient values compared with the physical therapist students in relation to the expert sonographer. Conclusions Excellent interrater reliability for US was observed regardless of the level of experience, severity of patient illness, or patient setting. These findings indicate that the use of muscle US by physical therapists can accurately capture reliable images in patients with a range of illness severity and different clinical practice settings across the continuum of care. Impact Physical therapists can utilize US to obtain images to assess muscle morphology. Lay Summary Physical therapists can use noninvasive US as an imaging tool to assess the size and quality of peripheral skeletal muscle. This study demonstrates that physical therapists can receive training to reliably obtain muscle images in patients admitted to the intensive care unit who may be at risk for muscle wasting and may benefit from early rehabilitation.

BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.

Cyclic compressive loading (CCL) is a massage mimetic that improves muscle regrowth from atrophy in adult rats. Therefore, we tested if a single bout of CCL increases anabolic signaling and protein synthesis in muscle during normal, weight-bearing conditions in gastrocnemius muscle from adult and aged rats. Male Brown Norway/F344 rats at 10 (adult) and 30 (aged) months of age were assigned control or CCL (receiving a single bout of CCL). Twenty-four hours following a single bout of CCL there was no change in protein synthesis, Akt, or GSK3β signaling at either age, despite adult rats having higher abundance and activation of mechanosensitive pathways (integrins and integrin-linked kinase). Murf1 was elevated in response to CCL in both age groups, potentially indicating muscle remodeling. Muscle from aged rats exhibited an increase in heat shock protein (HSP) 25 and HSP70 and in the cold shock protein RNA-binding motif 3 (RBM3), demonstrating a unique stress response to CCL in aged muscle only. Finally, muscle from aged rats exhibited higher basal protein synthesis that was corroborated by elevated eIF2Bε and rpS6 signaling, without an additional effect of CCL. In summary, a single bout of CCL does not have anabolic effects on skeletal muscle during normal, weight-bearing conditions, even though it has previously been shown to improve regrowth from atrophy. These data demonstrate that interventions that may help recover from atrophy do not necessarily induce muscle hypertrophy in unperturbed conditions. NEW & NOTEWORTHY Massage has been demonstrated to be an effective mechanotherapy to improve recovery from atrophy in adult skeletal muscle; however, this study shows that a single bout of massage fails to increase protein synthesis or anabolic signaling in adult or aged skeletal muscle during normal, weight-bearing conditions. Altogether, our data suggest massage is a useful mechanotherapy for preserving skeletal muscle when combined with other interventions but is not an anabolic stimulus on its own.

Supplemental Digital Content is available in the text., OBJECTIVES: Examine the safety and feasibility of a multimodal in-person or telehealth treatment program, administered in acute recovery phase for patients surviving critical coronavirus disease 2019. DESIGN: Pragmatic, pre-post, nonrandomized controlled trial with patients electing enrollment into one of the two recovery pathways. SETTING: ICU Recovery Clinic in an academic medical center. PATIENTS: Adult patients surviving acute respiratory failure due to critical coronavirus disease 2019. INTERVENTIONS: Patients participated in combined ICU Recovery clinic and 8 weeks of physical rehabilitation delivered: 1) in-person or 2) telehealth. Patients received medical care by an ICU Recovery Clinic interdisciplinary team and physical rehabilitation focused on aerobic, resistance, and respiratory muscle training. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients enrolled with mean age 57 ± 12, 62% were male, and the median Sequential Organ Failure Assessment score was 9.5. There were no differences between the two groups except patients in telehealth pathway (n = 10) lived further from clinic than face-to-face patients (162 ± 60 vs 31 ± 47 kilometers, t = 6.06, p < 0.001). Four safety events occurred: one minor adverse event in the telehealth group, two minor adverse events, and one major adverse event in the in-person group. Three patients did not complete the study (two in-person and one telehealth). Six-minute walk distance increased to 101 ± 91 meters from pre to post (n = 29, t = 6.93, p < 0.0001), which was similar between the two groups (110 vs 80 meters, t = 1.34, p = 0.19). Self-reported levels of anxiety, depression, and distress were high in both groups with similar self-report quality of life. CONCLUSIONS: A multimodal treatment program combining care from an interdisciplinary team in an ICU Recovery Clinic with physical rehabilitation is safe and feasible in patients surviving the ICU for coronavirus disease 2019 acute respiratory failure.

Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell-cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a period of time in the absence of satellite cells, but satellite cell participation is ultimately required to achieve full adaptive potential, be it growth, function, or proprioceptive coordination. While significant progress has been made in understanding the roles of satellite cells in adult muscle over the last few decades, many conclusions have been extrapolated from regeneration studies. This review highlights our current understanding of satellite cell behavior and contributions to adaptation outside of regeneration in adult muscle, as well as the roles of satellite cells beyond fusion and myonuclear accretion, which are gaining broader recognition.

Massage is a common therapeutic modality utilized by clinicians in a variety of settings to help treat injuries, reduce pain, and return function to patients. Massage benefits the patients both psychologically and physiologically, as patients report less pain and anxiety along with better mood and even decreased blood pressure following massage. Additionally, on the cellular level, massage has the ability to modulate the damaging inflammatory process and, in some cases, influence protein synthesis. Although massage has not been linked to a rehabilitation theory to date, this paper will propose how massage may influence fear-avoidance beliefs, or the patient’s inability to cope with pain that then leads to a pain tension cycle. Pain will often result in use avoidance, which creates muscle tension that further exacerbates the pain. Massage can affect the Fear-Avoidance Model because the beneficial effects of massage can break the cycle by either relieving the patient’s pain or eliminating the muscle tension. A modified Fear-Avoidance Model is presented that conceptualizes how pain and fear-avoidance lead to tension and muscle dysfunction. Massage has been incorporated into the model to demonstrate its potential for breaking the pain tension cycle. This model has the potential to be applied in clinical settings and provides an alternate treatment to patients with chronic pain who present with increased levels of fear-avoidance beliefs.

Skeletal muscle immune cells, such as macrophages, are necessary for proper regrowth following muscle disuse. We suggest that the important role of macrophages concerning muscle regrowth following disuse is divergent compared to young mice (i.e. dysregulated) during the recovery period. Modulation of macrophages may be a promising future therapeutic target to enhance the impaired muscle growth during recovery from disuse in older adults.

Objective The purpose of this case report is to provide the clinical presentation and physical therapist management for a patient with post–COVID syndrome. Secondarily, the report highlights the importance of assessing cognitive and emotional health in patients with post–COVID syndrome. Methods (Case Description) A 37-year-old woman tested positive for SARS-CoV-2 and developed mild COVID-19 disease but did not require supplemental oxygen or hospitalization. The patient experienced persistent symptoms, including dyspnea, headaches, and cognitive fog. On day 62, they participated in an outpatient physical therapist evaluation that revealed deficits in exercise capacity, obtaining 50% of their age-predicted 6-minute walk distance. They had minor reductions in muscle strength and cognitive function. Self-reported quality of life was 50, and they scored above established cut-off scores for provisional diagnosis of posttraumatic stress disorder (PTSD). Results The patient participated in biweekly physical therapist sessions for 8 weeks, which included aerobic training, strengthening exercises, diaphragmatic breathing techniques, and mindfulness training. Metabolic equivalent for task levels increased with variability over the course of the program. The patient’s muscle strength, physical function, and exercise capacity improved. 6-Minute walk distance increased by 199 m, equating to 80% of their age-predicted distance. Quality of life and PTSD scores did not improve. At evaluation after physical therapy, the patient was still experiencing migraines, dyspnea, fatigue, and cognitive dysfunction. Conclusion This case report described the clinical presentation and physical therapist management of a person with post–COVID syndrome, a novel health condition for which little evidence exists to guide rehabilitation examination and interventions. Physical therapists should consider cognitive function and emotional health in their plan of care for patients with post–COVID syndromes. Impact This case alerts physical therapists to post–COVID syndrome—which can include debilitating symptoms of decreased aerobic tolerance, anxiety, PTSD, and cognitive dysfunction—and to the role that therapists can play in assessing these symptoms and managing these patients.

Massage is anecdotally associated with many health benefits, but physiological and clinically relevant mechanisms recently have begun to be investigated in a controlled manner. Herein, we describe research supporting our hypothesis that massage can be used as a mechanotherapy imparting biologically relevant adaptations in skeletal muscle and improving muscle properties.

Low mobility during hospitalization remains prevalent despite associated negative consequences. The goal of this quality improvement (QI) project was to increase patient mobility and function by adding a physical therapist (PT) to an existing interprofessional care team. A mobility technician assisted treatment group patients with mobility during hospitalization based on physical therapist recommendations. Change in functional status and highest level of mobility achieved by treatment group patients was measured from admission to discharge. Observed hospital length of stay (LOS), LOS index, and 30-day all cause hospital readmission comparisons between treatment group and a comparison group on the same unit, and between cross-sectional comparison groups one year prior were used for Difference in Difference analysis. Bivariate comparisons between the treatment and a cross-sectional comparison group from one year prior showed a statistically significant change in LOS Index. No other bivariate comparisons were statistically significant. Difference in Difference methods showed no statistically significant change in observed LOS, LOS Index, or 30-day readmission. Patients in the treatment group had statistically significant improvements in functional status and highest level of mobility achieved. Physical function and mobility improved for patients who participated in mobility sessions. Mobility technicians may contribute to improved care quality and patient safety in the hospital.

Background In this case report, we describe the trajectory of recovery of a young, healthy patient diagnosed with coronavirus disease 2019 who developed acute respiratory distress syndrome. The purpose of this case report is to highlight the potential role of intensive care unit recovery or follow-up clinics for patients surviving acute hospitalization for coronavirus disease 2019. Case presentation Our patient was a 27-year-old Caucasian woman with a past medical history of asthma transferred from a community hospital to our medical intensive care unit for acute hypoxic respiratory failure due to bilateral pneumonia requiring mechanical ventilation (ratio of arterial oxygen partial pressure to fraction of inspired oxygen, 180). On day 2 of her intensive care unit admission, reverse transcription–polymerase chain reaction confirmed coronavirus disease 2019. Her clinical status gradually improved, and she was extubated on intensive care unit day 5. She had a negative test result for coronavirus disease 2019 twice with repeated reverse transcription–polymerase chain reaction before being discharged to home after 10 days in the intensive care unit. Two weeks after intensive care unit discharge, the patient returned to our outpatient intensive care unit recovery clinic. At follow-up, the patient endorsed significant fatigue and exhaustion with difficulty walking, minor issues with sleep disruption, and periods of memory loss. She scored 10/12 on the short performance physical battery, indicating good physical function. She did not have signs of anxiety, depression, or post-traumatic stress disorder through self-report questionnaires. Clinically, she was considered at low risk of developing post–intensive care syndrome, but she required follow-up services to assist in navigating the healthcare system, addressing remaining symptoms, and promoting return to her pre–coronavirus disease 2019 societal role. Conclusion We present this case report to suggest that patients surviving coronavirus disease 2019 with subsequent development of acute respiratory distress syndrome will require more intense intensive care unit recovery follow-up. Patients with a higher degree of acute illness who also have pre-existing comorbidities and those of older age who survive mechanical ventilation for coronavirus disease 2019 will require substantial post–intensive care unit care to mitigate and treat post–intensive care syndrome, promote reintegration into the community, and improve quality of life.

BACKGROUND Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3-adrenergic receptor agonist mirabegron induced beige adipose tissue in obese insulin-resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment and compared these with previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages. METHODS We measured BAT by PET CT scans, measured beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs. RESULTS Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments was evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The 3 treatments also had different effects on muscle fiber type switching and capillary density. CONCLUSION The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese insulin-resistant research participants. TRIAL REGISTRATION ClinicalTrials.gov NCT02919176. FUNDING NIH DK112282 and P20GM103527 and Clinical and Translational Science Awards grant UL1TR001998.

Small noncoding microRNAs (miRNAs) are important regulators of skeletal muscle size, and circulating miRNAs within extracellular vesicles (EVs) may contribute to atrophy and its associated systemic effects. The purpose of this study was to understand how muscle atrophy and regrowth alter in vivo serum EV miRNA content. We also associated changes in serum EV miRNA with protein synthesis, protein degradation, and miRNA within muscle, kidney, and liver. We subjected adult (10 mo) F344/BN rats to three conditions: weight bearing (WB), hindlimb suspension (HS) for 7 days to induce muscle atrophy, and HS for 7 days followed by 7 days of reloading (HSR). Microarray analysis of EV miRNA content showed that the overall changes in serum EV miRNA were predicted to target major anabolic, catabolic, and mechanosensitive pathways. MiR-203a-3p was the only miRNA demonstrating substantial differences in HS EVs compared with WB. There was a limited association of EV miRNA content to the corresponding miRNA content within the muscle, kidney, or liver. Stepwise linear regression demonstrated that EV miR-203a-3p was correlated with muscle mass and muscle protein synthesis and degradation across all conditions. Finally, EV miR-203a-3p expression was significantly decreased in human subjects who underwent unilateral lower limb suspension (ULLS) to induce muscle atrophy. Altogether, we show that serum EV miR-203a-3p expression is related to skeletal muscle protein turnover and atrophy. We suggest that serum EV miR-203a-3p content may be a useful biomarker and future work should investigate whether serum EV miR-203a-3p content is mechanistically linked to protein synthesis and degradation.

Treatment of subjects who are obese/insulin resistant with the β3AR agonist mirabegron resulted in increased beige adipose tissue, without a change in brown adipose tissue (BAT), along with an improvement in glucose tolerance, HbA1c, and an increase in type 1 fibers in skeletal muscle. Pioglitazone has been demonstrated to increase beiging, and it has been demonstrated that combination of a thiazolidinedione with a β3AR agonist further increased beige adipocyte markers in vitro. The goal of this study was to determine whether combination therapy with pioglitazone and mirabegron would further increase beiging, BAT volume or activity, or skeletal muscle fiber type switching, and improve glucose homeostasis more than each drug separately. We randomized obese and insulin-resistant (IR) research participants to mirabegron (50 mg/day), pioglitazone (30 mg/day), or combination treatment groups. Adipose and muscle tissue biopsies and PET-CT scans were performed at baseline and after 10 weeks of treatment. Mitochondrial bioenergetics were determined in purified mitochondria from adipose tissue. Although mirabegron and pioglitazone treatment significantly induced SC WAT beiging separately, the combination of the two drugs resulted in less beiging than mirabegron treatment alone, and did not increase mitochondrial uncoupling. Furthermore, neither pioglitazone nor combination therapy increased BAT or fiber-type switching to type 1 fibers. Although each drug improved glucose homeostasis, the effect of the combination was not significantly additive. Analysis of mRNA expression revealed that pioglitazone or combination treatment induced the expression of p107, which promotes white versus brown adipose gene expression, suggesting a mechanism for inhibition of mirabegron-induced beiging by pioglitazone. These results suggest that pioglitazone inhibits mirabegron-induced beiging and does not augment other beneficial effects of mirabegron treatment. Disclosure P.A. Kern: None. H. Memetimin: None. B. Zhu: None. A.L. Confides: None. Z. Johnson: None. H.J. Vekaria: None. P. Westgate: None. P.G. Sullivan: None. E.E. Dupont-Versteegden: None. B. Finlin: None. Funding National Institutes of Health (DK112282)

Introduction The primary objective of this study was to determine whether pretransplant physical function is correlated with posttransplantation outcomes. Methods We performed a retrospective study of patients that participated in pretransplantation screening and subsequently underwent lung transplantation. Pretransplant variables of interest included demographics, muscle mass, body composition, physical function, and physical frailty. Correlation tests were performed to assess relationships with significance set at 0.05. Results Twenty-five patients with a mean age of 57 ± 13 years (68% male) with pretransplant lung allocation score of 45 ± 14 were included. This cohort had a 3-year mortality rate of 32% (n = 8). Pretransplant 4-m gait speed was significantly related to performance on the Short Physical Performance Battery (r = 0.74, P = .02) and distance ambulated on the 6-minute walk test (r = 0.62, P = .07) at hospital discharge. Older age was associated with slower gait speed and worse performance on sit-to-stand testing at hospital discharge (r = −0.76, P = .01 and r = −0.75, P = .01, respectively). Statistically, only diagnosis of cystic fibrosis was associated with 3-year mortality. Discussion Our study demonstrates that demographic, clinical, and physical function assessed prior to lung transplantation may be indicators of functional recovery.

Background Up to 66% of patients admitted to the intensive care unit (ICU) for acute respiratory failure (ARF) develop ICU-acquired weakness, which is diagnosed by muscle strength testing. Muscle power, different from strength, is an important determinant of function that is not a common focus in patients surviving critical illness. Therefore, the purpose of this study is to assess muscle power in survivors of ARF. Methods A cross-sectional observational study performed with survivors of ARF. Muscle power, strength and physical function were assessed 4–8 weeks post-hospital discharge. Cross sectional area and echogenicity of rectus femoris and tibialis anterior muscles were assessed using ultrasonography. Healthy community-dwelling adults were included for comparison. Results 12 survivors of ARF mean age of 55.6 ± 17.1 (66% male) and 12 healthy adults mean age of 51.6.1 ± 10.3 (66% male) participated in this study. Patients in the post-ARF group had a mean muscle power of 9.9 ± 3.5 W and 63.7 ± 31.6 W for 2-lb and 10% of body-weight loads, respectively. Compared to matched controls, power in ARF group was reduced by 43%. Muscle power in post-ARF group had moderate correlations with 5-times sit-to-stand testing (r = -0.644, P = 0.024), 4-m habitual gait speed (-0.780, P = 0.002), and 6-min walk distance (r = 0.589, P = 0.044). Conclusions Muscle power is significantly reduced in survivors of critical illness and associated with deficits in physical function. These preliminary findings may support therapeutic interventions aimed at improving muscle power to potentially increase functional benefit.

Aim Interventions that decrease atrophy during disuse are desperately needed to maintain muscle mass. We recently found that massage as a mechanotherapy can improve muscle regrowth following disuse atrophy. Therefore, we aimed to determine if massage has similar anabolic effects when applied during normal weight bearing conditions (WB) or during atrophy induced by hindlimb suspension (HS) in adult rats. Methods Adult (10 months) male Fischer344-Brown Norway rats underwent either hindlimb suspension (HS, n = 8) or normal WB (WB, n = 8) for 7 days. Massage was applied using cyclic compressive loading (CCL) in WB (WBM, n = 9) or HS rats (HSM, n = 9) and included four 30-minute bouts of CCL applied to gastrocnemius muscle every other day. Results Massage had no effect on any anabolic parameter measured under WB conditions (WBM). In contrast, massage during HS (HSM) stimulated protein turnover, but did not mitigate muscle atrophy. Atrophy from HS was caused by both lowered protein synthesis and higher degradation. HS and HSM had lowered total RNA compared with WB and this was the result of significantly higher ribosome degradation in HS that was attenuated in HSM, without differences in ribosomal biogenesis. Also, massage increased protein turnover in the non-massaged contralateral limb during HS. Finally, we determined that total RNA degradation primarily dictates loss of muscle ribosomal content during disuse atrophy. Conclusion We conclude that massage is an effective mechanotherapy to impact protein turnover during muscle disuse in both the massaged and non-massaged contralateral muscle, but it does not attenuate the loss of muscle mass.