Skeletal muscle loss after laparoscopic gastrectomy assessed by measuring the total psoas area.

PURPOSE: Skeletal muscle loss after gastrectomy can worsen patients' quality of life and prognosis. Laparoscopic gastrectomy is less invasive than open gastrectomy and has become commonly performed. However, the degree of skeletal muscle loss after laparoscopic procedures remains unclear. We herein report the degree and risk factors of psoas muscle loss after laparoscopic gastrectomy for gastric cancer. METHODS: The total psoas area (TPA) on computed tomography of 50 consecutive patients who underwent laparoscopic total gastrectomy (LTG) and 167 consecutive patients who underwent laparoscopic distal gastrectomy (LDG) for gastric cancer was retrospectively evaluated at one postoperative year. The TPA loss was compared between LDG and LTG and univariate and multivariate analyses were performed to identify the risk factors for TPA loss > 10%. RESULTS: The median TPA decrease rate was 5.9% in the LDG group and 15.6% in the LTG group. LTG and postoperative respiratory complications were independent factors associated with a severe TPA loss of > 10%. In the LTG group, no independent factors were identified in a multivariate analysis. In the LDG group, postoperative complications were identified as an independent risk factor for TPA loss > 10%. CONCLUSIONS: Laparoscopic gastrectomy leads to postoperative TPA loss, especially in patients who underwent LTG and had postoperative respiratory complications. Postoperative complications after LDG were also a risk factor for TPA loss.

Low-Frequency Electrical Stimulation of Denervated Skeletal Muscle Retards Muscle and Trabecular Bone Loss in Aged Rats.

Electrical stimulation (ES)-induced muscle contraction has multiple effects; however, mechano-responsiveness of bone tissue declines with age. Here, we investigated whether daily low-frequency ES-induced muscle contraction treatment reduces muscle and bone loss and ameliorates bone fragility in early-stage disuse musculoskeletal atrophy in aged rats. Twenty-seven-month-old male rats were assigned to age-matched groups comprising the control (CON), sciatic nerve denervation (DN), or DN with direct low-frequency ES (DN+ES) groups. The structural and mechanical properties of the trabecular and cortical bone of the tibiae, and the morphological and functional properties of the tibialis anterior (TA) muscles were assessed one week after DN. ES-induced muscle contraction force mitigated denervation-induced muscle and trabecular bone loss and deterioration of the mechanical properties of the tibia mid-diaphysis, such as the stiffness, but not the maximal load, in aged rats. The TA muscle in the DN+ES group showed significant improvement in the myofiber cross-sectional area and muscle force relative to the DN group. These results suggest that low-frequency ES-induced muscle contraction treatment retards trabecular bone and muscle loss in aged rats in early-stage disuse musculoskeletal atrophy, and has beneficial effects on the functional properties of denervated skeletal muscle.

Disuse Atrophy Accompanied by Intramuscular Ectopic Adipogenesis in Vastus Medialis Muscle of Advanced Osteoarthritis Patients.

Muscle dysfunction is the most important modifiable mediating factor in primary osteoarthritis (OA) because properly contracting muscles are a key absorber of forces acting on a joint. However, the pathological features of disuse muscle atrophy in OA patients have been rarely studied. Vastus medialis muscles of 14 female patients with OA (age range, 69 to 86 years), largely immobile for 1 or more years, were obtained during arthroplastic surgery and analyzed histologically. These were compared with female patients without arthritis, two with patellar fracture and two with patellar subluxation. Areas occupied by myofibers and adipose tissue were quantified. Large numbers of myofibers were lost in the vastus medialis of OA patients. The loss of myofibers was a possible cause of the reduction in muscle strength of the operated on knee. These changes were significantly correlated with an increase in intramuscular ectopic adipose tissue, and not observed in knees of nonarthritic patients. Resident platelet-derived growth factor receptor α-positive mesenchymal progenitor cells contributed to ectopic adipogenesis in vastus medialis muscles of OA patients. The present study suggests that significant loss of myofibers and ectopic adipogenesis in vastus medialis muscles are common pathological features of advanced knee OA patients with long-term loss of mobility. These changes may be related to the loss of joint function in patients with knee OA.

Effects of post-fracture non-weight-bearing immobilization on muscle atrophy, intramuscular and intermuscular adipose tissues in the thigh and calf.

OBJECTIVE: Disuse and/or a non-weight-bearing condition changes muscle composition, with decreased skeletal muscle tissue and increased fat within (intramuscular adipose tissue, IntraMAT) and between (intermuscular adipose tissue, InterMAT) given muscles. Excessive adipose tissue contributes to dysfunctional and metabolically impaired muscle. How these adipose tissues change during orthopedic treatment (e.g., cast immobilization, daily use of crutches) is not well documented. This study aimed to quantify changes in IntraMAT, InterMAT, and thigh and calf muscle tissue during orthopedic treatment. MATERIALS AND METHODS: We studied 8 patients with fifth metatarsal bone or fibular fractures. The ankle joint involved underwent plaster casting for approximately 4 weeks, with crutches used during that time. Axial T1-weighted MRI at the mid-thigh and a 30% proximal site at the calf were obtained to measure IntraMAT and InterMAT cross-sectional areas (CSAs) and skeletal muscle tissue CSA before treatment and 4 weeks afterward. RESULTS: Thigh and calf muscle tissue CSAs were significantly decreased from before to after treatment: thigh, 85.8 ± 7.6 to 77.1 ± 7.3 cm2; calf, 53.3 ± 5.5 to 48.9 ± 5.0 cm2 (p < 0.05). None of the IntraMAT or InterMAT changes was statistically significant. There was a relation between the percentage change of thigh IntraMAT CSA and muscle tissue CSA (rs = -0.86, p < 0.01). CONCLUSIONS: The 4 weeks of treatment primarily induced skeletal muscle atrophy with less of an effect on IntraMAT or InterMAT. There is a risk of increasing IntraMAT relatively by decreasing skeletal muscle tissue size during orthopedic treatment.

Resistance exercise training in patients with genitourinary cancers to mitigate treatment-related skeletal muscle loss.

The use of targeted therapies in patients with genitourinary malignancies has significantly improved outcomes. For example, androgen receptor (AR) pathway inhibitors have improved outcomes for patients with prostate cancer, and antiangiogenic agents have improved outcomes for those with kidney cancer. However, these advances have been accompanied by musculoskeletal side effects that manifest as physical dysfunction. Although the effects of androgen deprivation therapy on skeletal muscle are well-known, an additional concern is that the muscle loss associated with these newer drugs-especially AR pathway inhibitors-may result in insulin resistance and metabolic syndrome, thus increasing the risk for cardiovascular events and diabetes. Antiangiogenic agents also may cause muscle loss, although this has been poorly described in the literature. As these targeted therapies begin to be used in the earlier stages of treatment, there will be a critical need to prevent treatment-related toxicities with nonpharmacologic interventions. Over the past decade, exercise training has emerged as a novel nonpharmacologic adjunctive method to address toxicities resulting from these targeted therapies. Despite numerous studies in patients with prostate cancer, there remains a large gap in our knowledge of the true efficacy of exercise therapy, as well as the best way to prescribe exercise programs. Here, we suggest that the central role of skeletal muscle in the development of side effects of AR pathway inhibitors and antiangiogenic agents may unlock a number of unique opportunities to study how exercise prescriptions can be used more effectively. Resistance training may be a particularly important modality.

Effects of exercise on soleus in severe burn and muscle disuse atrophy.

BACKGROUND: Muscle loss is a sequela of severe burn and critical illness with bed rest contributing significantly to atrophy. We hypothesize that exercise will mitigate muscle loss after burn with bed rest. MATERIALS AND METHODS: Male rats were assigned to sham ambulatory (S/A), burn ambulatory (B/A), sham hindlimb unloading (S/H), or burn hindlimb unloading (B/H). Rats received a 40% scald burn or sham and were ambulatory or placed in hindlimb unloading, a model of bed rest. Half from each group performed twice daily resistance climbing. Hindlimb isometric forces were measured on day 14. RESULTS: Soleus mass and muscle function were not affected by burn alone. Mass was significantly lower in hindlimb unloading (79 versus 139 mg, P < 0.001) and no exercise (103 versus 115 mg, P < 0.01). Exercise significantly increased soleus mass in B/H (86 versus 77 mg, P < 0.01). Hindlimb unloading significantly decreased muscle force in the twitch (12 versus 31 g, P < 0.001), tetanic (55 versus 148 g, P < 0.001), and specific tetanic measurements (12 versus 22 N/cm(2), P < 0.001). Effects of exercise on force depended on other factors. In B/H, exercise significantly increased twitch (14 versus 8 g, P < 0.05) and specific tetanic force (14 versus 7 N/cm(2), P < 0.01). Fatigue index was lower in ambulatory (55%) and exercise (52%) versus hindlimb (69%, P = 0.03) and no exercise (73%, P = 0.002). CONCLUSIONS: Hindlimb unloading is a significant factor in muscle atrophy. Exercise increased the soleus muscle mass, twitch, and specific force in this model. However, the fatigue index decreased with exercise in all groups. This suggests exercise contributes to functional muscle change in this model of disuse and critical illness.

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness.

BACKGROUND: Skeletal muscle wasting and weakness are significant complications of critical illness, associated with degree of illness severity and periods of reduced mobility during mechanical ventilation. They contribute to the profound physical and functional deficits observed in survivors. These impairments may persist for many years following discharge from the intensive care unit (ICU) and can markedly influence health-related quality of life. Rehabilitation is a key strategy in the recovery of patients after critical illness. Exercise-based interventions are aimed at targeting this muscle wasting and weakness. Physical rehabilitation delivered during ICU admission has been systematically evaluated and shown to be beneficial. However, its effectiveness when initiated after ICU discharge has yet to be established. OBJECTIVES: To assess the effectiveness of exercise rehabilitation programmes, initiated after ICU discharge, for functional exercise capacity and health-related quality of life in adult ICU survivors who have been mechanically ventilated longer than 24 hours. SEARCH METHODS: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid SP MEDLINE, Ovid SP EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO host to 15 May 2014. We used a specific search strategy for each database. This included synonyms for ICU and critical illness, exercise training and rehabilitation. We searched the reference lists of included studies and contacted primary authors to obtain further information regarding potentially eligible studies. We also searched major clinical trials registries (Clinical Trials and Current Controlled Trials) and the personal libraries of the review authors. We applied no language or publication restriction. We reran the search in February 2015 and will deal with the three studies of interest when we update the review. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs and controlled clinical trials (CCTs) that compared an exercise intervention initiated after ICU discharge versus any other intervention or a control or 'usual care' programme in adult (≥ 18 years) survivors of critical illness. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by the Cochrane Collaboration. MAIN RESULTS: We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both on the ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to length of hospital stay following ICU discharge (up to a fixed duration of 12 weeks).Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. For other domains, at least half of the studies were at low risk of bias. One study was at high risk of selection bias, attrition bias and other sources of bias. Risk of bias was unclear for the remaining studies across domains. We decided not to undertake a meta-analysis because of variation in study design, types of interventions and outcome measurements. We present a narrative description of individual studies for each outcome.All six studies assessed functional exercise capacity, although we noted wide variability in the nature of interventions, outcome measures and associated metrics and data reporting. Overall quality of the evidence was very low. Individually, three studies reported positive results in favour of the intervention. One study found a small short-term benefit in anaerobic threshold (mean difference (MD) 1.8 mL O2/kg/min, 95% confidence interval (CI) 0.4 to 3.2; P value = 0.02). In a second study, both incremental (MD 4.7, 95% CI 1.69 to 7.75 watts; P value = 0.003) and endurance (MD 4.12, 95% CI 0.68 to 7.56 minutes; P value = 0.021) exercise testing results were improved with intervention. Finally self reported physical function increased significantly following use of a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.Similar variability was evident with regard to findings for the primary outcome of health-related quality of life. Only two studies evaluated this outcome. Individually, neither study reported differences between intervention and control groups for health-related quality of life due to the intervention. Overall quality of the evidence was very low.Four studies reported rates of withdrawal, which ranged from 0% to 26.5% in control groups, and from 8.2% to 27.6% in intervention groups. The quality of evidence for the effect of the intervention on withdrawal was low. Very low-quality evidence showed rates of adherence with the intervention. Mortality ranging from 0% to 18.8% was reported by all studies. The quality of evidence for the effect of the intervention on mortality was low. Loss to follow-up, as reported in all studies, ranged from 0% to 14% in control groups, and from 0% to 12.5% in intervention groups, with low quality of evidence. Only one non-mortality adverse event was reported across all participants in all studies (a minor musculoskeletal injury), and the quality of the evidence was low. AUTHORS' CONCLUSIONS: At this time, we are unable to determine an overall effect on functional exercise capacity, or on health-related quality of life, of an exercise-based intervention initiated after ICU discharge for survivors of critical illness. Meta-analysis of findings was not appropriate because the number of studies and the quantity of data were insufficient. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others did not. No effect on health-related quality of life was reported. Methodological rigour was lacking across several domains, influencing the quality of the evidence. Wide variability was noted in the characteristics of interventions, outcome measures and associated metrics and data reporting.If further trials are identified, we may be able to determine the effects of exercise-based intervention following ICU discharge on functional exercise capacity and health-related quality of life among survivors of critical illness.

Activation of alternative NF-κB signaling during recovery of disuse-induced loss of muscle oxidative phenotype.

Physical inactivity-induced loss of skeletal muscle oxidative phenotype (OXPHEN), often observed in chronic disease, adversely affects physical functioning and quality of life. Potential therapeutic targets remain to be identified, since the molecular mechanisms involved in reloading-induced recovery of muscle OXPHEN remain incompletely understood. We hypothesized a role for alternative NF-κB, as a recently identified positive regulator of muscle OXPHEN, in reloading-induced alterations in muscle OXPHEN. Markers and regulators (including alternative NF-κB signaling) of muscle OXPHEN were investigated in gastrocnemius muscle of mice subjected to a hindlimb suspension/reloading (HLS/RL) protocol. Expression levels of oxidative phosphorylation subunits and slow myosin heavy chain isoforms I and IIA increased rapidly upon RL. After an initial decrease upon HLS, mRNA levels of peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC) molecules PGC-1α and PGC-1ß and mRNA levels of mitochondrial transcription factor A (Tfam) and estrogen-related receptor α increased upon RL. PPAR-δ, nuclear respiratory factor 1 (NRF-1), NRF-2α, and sirtuin 1 mRNA levels increased during RL although expression levels were unaltered upon HLS. In addition, both Tfam and NRF-1 protein levels increased significantly during the RL period. Moreover, upon RL, IKK-α mRNA and protein levels increased, and phosphorylation of P100 and subsequent processing to P52 were elevated, reflecting alternative NF-κB activation. We conclude that RL-induced recovery of muscle OXPHEN is associated with activation of alternative NF-κB signaling.

Spinal and bulbar muscular atrophy: pathogenesis and clinical management.

Spinal and bulbar muscular atrophy, or Kennedy's disease, is an X-linked motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. The disease is characterised by weakness, atrophy and fasciculations in the limb and bulbar muscles. Affected males may have signs of androgen insensitivity, such as gynaecomastia and reduced fertility. Neurophysiological studies are typically consistent with diffuse denervation atrophy, and serum creatine kinase is usually elevated 2-5 times above normal. Progression of the disease is slow, and the focus of spinal and bulbar muscular atrophy (SBMA) management is to prevent complications.

Age-related differences in the loss and recovery of serial sarcomere number following disuse atrophy in rats.

BACKGROUND: Older adults exhibit a slower recovery of muscle mass following disuse atrophy than young adults. At a smaller scale, muscle fibre cross-sectional area (i.e., sarcomeres in parallel) exhibits this same pattern. Less is known, however, about age-related differences in the recovery of muscle fibre length, driven by increases in serial sarcomere number (SSN), following disuse. The purpose of this study was to investigate age-related differences in SSN adaptations and muscle mechanical function during and following muscle immobilization. We hypothesized that older adult rats would experience a similar magnitude of SSN loss during immobilization, however, take longer to recover SSN than young following cast removal, which would limit the recovery of muscle mechanical function. METHODS: We casted the plantar flexors of young (8 months) and old (32 months) male rats in a shortened position for 2 weeks, and assessed recovery during 4 weeks of voluntary ambulation. Following sacrifice, legs were fixed in formalin for measurement of soleus SSN and physiological cross-sectional area (PCSA) with the un-casted soleus acting as a control. Ultrasonographic measurements of pennation angle (PA) and muscle thickness (MT) were conducted weekly. In-vivo active and passive torque-angle relationships were constructed pre-cast, post-cast, and following 4 weeks of recovery. RESULTS: From pre- to post-cast, young and older adult rats experienced similar decreases in SSN (-20%, P < 0.001), muscle wet weight (-25%, P < 0.001), MT (-30%), PA (-15%, P < 0.001), and maximum isometric torque (-40%, P < 0.001), but there was a greater increase in passive torque in older (+ 180%, P < 0.001) compared to young adult rats (+ 68%, P = 0.006). Following cast removal, young exhibited quicker recovery of SSN and MT than old, but SSN recovered sooner than PA and MT in both young and old. PCSA nearly recovered and active torque fully recovered in young adult rats, whereas in older adult rats these remained unrecovered at ∼ 75%. CONCLUSIONS: This study showed that older adult rats retain a better ability to recover longitudinal compared to parallel muscle morphology following cast removal, making SSN a highly adaptable target for improving muscle function in elderly populations early on during rehabilitation.

Mitochondrial signaling contributes to disuse muscle atrophy.

It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

Preserving sarcomere number after tenotomy requires stretch and contraction.

INTRODUCTION: Passive stretch therapy is utilized to improve the range of motion of chronically shortened muscles. However, human studies show conflicting results as whether passive stretch is clinically effective. METHODS: The soleus muscles of adult rats were tenotomized to induce muscle shortening adaptation. Muscles included were non-treated normal, subjected to daily static stretch, or lengthened and isometrically contracted for 20 min/day. Muscle fiber structure was analyzed histochemically. Sarcomeres per millimeter length were counted to assess the effect of treatment. RESULTS: Passive stretch significantly reduced central core lesion formation, but sarcomere loss was not prevented. The addition of isometric contraction during static stretch significantly (P < 0.001) reduced sarcomere loss. CONCLUSIONS: Passive stretch alone does not prevent shortening adaptation. Contraction is required in combination with stretch to preserve the number of sarcomeres in series. The combination of stretch and contraction is necessary to maintain proper muscle fiber length.

The time course of disuse muscle atrophy of the lower limb in health and disease.

Short, intermittent episodes of disuse muscle atrophy (DMA) may have negative impact on age related muscle loss. There is evidence of variability in rate of DMA between muscles and over the duration of immobilization. As yet, this is poorly characterized. This review aims to establish and compare the time-course of DMA in immobilized human lower limb muscles in both healthy and critically ill individuals, exploring evidence for an acute phase of DMA and differential rates of atrophy between and muscle groups. MEDLINE, Embase, CINHAL and CENTRAL databases were searched from inception to April 2021 for any study of human lower limb immobilization reporting muscle volume, cross-sectional area (CSA), architecture or lean leg mass over multiple post-immobilization timepoints. Risk of bias was assessed using ROBINS-I. Where possible meta-analysis was performed using a DerSimonian and Laird random effects model with effect sizes reported as mean differences (MD) with 95% confidence intervals (95% CI) at various time-points and a narrative review when meta-analysis was not possible. Twenty-nine studies were included, 12 in healthy volunteers (total n = 140), 18 in patients on an Intensive Therapy Unit (ITU) (total n = 516) and 3 in patients with ankle fracture (total n = 39). The majority of included studies are at moderate risk of bias. Rate of quadriceps atrophy over the first 14 days was significantly greater in the ITU patients (MD -1.01 95% CI -1.32, -0.69), than healthy cohorts (MD -0.12 95% CI -0.49, 0.24) (P < 0.001). Rates of atrophy appeared to vary between muscle groups (greatest in triceps surae (-11.2% day 28), followed by quadriceps (-9.2% day 28), then hamstrings (-6.5% day 28), then foot dorsiflexors (-3.2% day 28)). Rates of atrophy appear to decrease over time in healthy quadriceps (-6.5% day 14 vs. -9.1% day 28) and triceps surae (-7.8% day 14 vs. -11.2% day 28), and ITU quadriceps (-13.2% day 7 vs. -28.2% day 14). There appears to be variability in the rate of DMA between muscle groups, and more rapid atrophy during the earliest period of immobilization, indicating different mechanisms being dominant at different timepoints. Rates of atrophy are greater amongst critically unwell patients. Overall evidence is limited, and existing data has wide variability in the measures reported. Further work is required to fully characterize the time course of DMA in both health and disease.

Tetanic contractions impair sarcomeric Z-disk of atrophic soleus muscle via calpain pathway.

The aim of this study was to determine whether or not over-activation of calpains during running exercise or tetanic contractions was a major factor to induce sarcomere lesions in atrophic soleus muscle. Relationship between the degrees of desmin degradation and sarcomere lesions was also elucidated. We observed ultrastructural changes in soleus muscle fibers after 4-week unloading with or without running exercise. Calpain activity and desmin degradation were measured in atrophic soleus muscles before or after repeated tetani in vitro. Calpain-1 activity was progressively increased and desmin degradation was correspondingly elevated in 1-, 2-, and 4-week of unloaded soleus muscles. Calpain-1 activity and desmin degradation had an additional increase in unloaded soleus muscles after repeated tetani in vitro. PD150606, an inhibitor of calpains, reduced calpain activity and desmin degradation during tetanic contractions in unloaded soleus muscles. The 4-week unloading decreased the width of myofibrils and Z-disk in soleus fibers. After running exercise in unloaded group, Z-disks of adjacent myofibrils were not well in register but instead were longitudinally displaced. Calpain inhibition compromised exercise-induced misalignment of the Z-disks in atrophic soleus muscle. These results suggest that tetanic contractions induce an over-activation of calpains which lead to higher degrees of desmin degradation in unloaded soleus muscle. Desmin degradation may loose connections between adjacent myofibrils, whereas running exercise results in sarcomere injury in unloaded soleus muscle.

Female mice may have exacerbated catabolic signalling response compared to male mice during development and progression of disuse atrophy.

BACKGROUND: Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well-established model of hindlimb unloading (HU). METHODS: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism). RESULTS: Both males and females lost ~30% of tibialis anterior cross-sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross-sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24-48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4-fold greater content in females compared with ~2-fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes. CONCLUSIONS: These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy.

The impact of hindlimb disuse on sepsis-induced myopathy in mice.

Sepsis induces a myopathy characterized by loss of muscle mass and weakness. Septic patients undergo prolonged periods of limb muscle disuse due to bed rest. The contribution of limb muscle disuse to the myopathy phenotype remains poorly described. To characterize sepsis-induced myopathy with hindlimb disuse, we combined the classic sepsis model via cecal ligation and puncture (CLP) with the disuse model of hindlimb suspension (HLS) in mice. Male C57bl/6j mice underwent CLP or SHAM surgeries. Four days after surgeries, mice underwent HLS or normal ambulation (NA) for 7 days. Soleus (SOL) and extensor digitorum longus (EDL) were dissected for in vitro muscle mechanics, morphological, and histological assessments. In SOL muscles, both CLP+NA and SHAM+HLS conditions elicited ~20% reduction in specific force (p < 0.05). When combined, CLP+HLS elicited ~35% decrease in specific force (p < 0.05). Loss of maximal specific force (~8%) was evident in EDL muscles only in CLP+HLS mice (p < 0.05). CLP+HLS reduced muscle fiber cross-sectional area (CSA) and mass in SOL (p < 0.05). In EDL muscles, CLP+HLS decreased absolute mass to a smaller extent (p < 0.05) with no changes in CSA. Immunohistochemistry revealed substantial myeloid cell infiltration (CD68+) in SOL, but not in EDL muscles, of CLP+HLS mice (p < 0.05). Combining CLP with HLS is a feasible model to study sepsis-induced myopathy in mice. Hindlimb disuse combined with sepsis induced muscle dysfunction and immune cell infiltration in a muscle dependent manner. These findings highlight the importance of rehabilitative interventions in septic hosts to prevent muscle disuse and help attenuate the myopathy.

Split phenomenon of antagonistic muscle groups in amyotrophic lateral sclerosis: relative preservation of flexor muscles.

Objective: In addition to the split hand sign, other split phenomena of different muscles also exist in amyotrophic lateral sclerosis (ALS). We analyzed the incidence of split phenomena in multiple antagonistic muscle groups in ALS patients and explored whether clinical factors affected their occurrence.Methods: 618 ALS patients were included from a single ALS center. Muscle strength in upper and lower limbs was evaluated using the modified Medical Research Council (MRC) scoring system (range from 1 to 13). Split phenomena between different antagonistic muscle groups were summarized, and the correlations with clinical factors were analyzed.Results: Split phenomena were detected in 22.3% antagonistic muscles for flexion and extension of the elbow, 11.9% for the wrist, 23.9% for fingers, 18.2% for the ankle, and 14.7% for toes. These manifestations were characterized by preferential wasting of the elbow, wrist, and finger extensor muscles compared with the flexor muscles, and the ankle and toe dorsiflexor muscles compared with the plantar flexor muscles. The presence of muscle wasting was more common when the muscle strength was stronger than a modified MRC grade 6. No definite correlation was found between split phenomena and clinical factors, including age-at-onset, gender, disease duration, the region of onset, and pyramidal tract damage.Discussion: Split phenomena of antagonistic muscle groups widely exist in ALS patients. No definitive and consistent clinical factors were observed that affected the occurrence of these phenomena.

Angiotensin 1-7 protects against ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is a life-saving instrument used to provide ventilatory support for critically ill patients and patients undergoing surgery. Unfortunately, an unintended consequence of prolonged MV is the development of inspiratory weakness due to both diaphragmatic atrophy and contractile dysfunction; this syndrome is labeled ventilator-induced diaphragm dysfunction (VIDD). VIDD is clinically important because diaphragmatic weakness is an important contributor to problems in weaning patients from MV. Investigations into the pathogenesis of VIDD reveal that oxidative stress is essential for the rapid development of VIDD as redox disturbances in diaphragm fibers promote accelerated proteolysis. Currently, no standard treatment exists to prevent VIDD and, therefore, developing a strategy to avert VIDD is vital. Guided by evidence indicating that activation of the classical axis of the renin-angiotensin system (RAS) in diaphragm fibers promotes oxidative stress and VIDD, we hypothesized that activation of the nonclassical RAS signaling pathway via angiotensin 1-7 (Ang1-7) will protect against VIDD. Using an established animal model of prolonged MV, our results disclose that infusion of Ang1-7 protects the diaphragm against MV-induced contractile dysfunction and fiber atrophy in both fast and slow muscle fibers. Further, Ang1-7 shielded diaphragm fibers against MV-induced mitochondrial damage, oxidative stress, and protease activation. Collectively, these results reveal that treatment with Ang1-7 protects against VIDD, in part, due to diminishing oxidative stress and protease activation. These important findings provide robust evidence that Ang1-7 has the therapeutic potential to protect against VIDD by preventing MV-induced contractile dysfunction and atrophy of both slow and fast muscle fibers.

The impact of muscle disuse on muscle atrophy in severely burned rats.

BACKGROUND: Severe burn induces a sustained hypermetabolic response, which causes long-term loss of muscle mass and decrease in muscle strength. In this study, we sought to determine whether muscle disuse has additional impact on muscle atrophy after severe burn using a rat model combining severe cutaneous burn and hindlimb unloading. METHODS: Forty Sprague-Dawley rats (≈ 300 g) were randomly assigned to sham ambulatory (S/A), sham hindlimb unloading (S/HLU), burn ambulatory (B/A), or burn hindlimb unloading (B/HLU) groups. Rats received a 40% total body surface (TBSA) full thickness scald burn, and rats with hindlimb unloading were placed in a tail traction system. At d 14, lean body mass (LBM) was determined using DEXA scan, followed by measurement of the isometric mechanical properties in the predominantly fast-twitch plantaris muscle (PL) and the predominantly slow-twitch soleus muscle (SL). Muscle weight (wt), protein wt, and wet/dry wt were determined. RESULTS: At d 14, body weight had decreased significantly in all treatment groups; B/HLU resulted in significantly greater loss compared with the B/A, S/HLU, and S/A. The losses could be attributed to loss of LBM. PL muscle wt and Po were lowest in the B/HLU group (<0.05 versus S/A, S/HLU, or B/A). SL muscle wt and Po were significantly less in both S/HLU and B/HLU compared with that of S/A and B/A; no significant difference was found between S/HLU and B/HLU. CONCLUSIONS: Cutaneous burn and hindlimb unloading have an additive effect on muscle atrophy, characterized by loss of muscle mass and decrease in muscle strength in both fast (PL) and slow (SL) twitch muscles. Of the two, disuse appeared to be the dominant factor for continuous muscle wasting after acute burn in this model.