Disuse muscle atrophy (DMA) is a significant healthcare challenge characterized by progressive loss of muscle mass and function resulting from prolonged inactivity. The development of effective strategies for muscle recovery is essential. In this study, we established a DMA mouse model through hindlimb suspension to evaluate the therapeutic potential of lactate in alleviating the detrimental effects on the gastrocnemius muscle. Using NMR-based metabolomic analysis, we investigated the metabolic changes in DMA-injured gastrocnemius muscles compared to controls and evaluated the beneficial effects of lactate treatment. Our results show that lactate significantly reduced muscle mass loss and improved muscle function by downregulating Murf1 expression, decreasing protein ubiquitination and hydrolysis, and increasing myosin heavy chain levels. Crucially, lactate corrected perturbations in four key metabolic pathways in the DMA gastrocnemius: the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; histidine metabolism; and arginine and proline metabolism. In addition to phenylalanine-related pathways, lactate also plays a role in regulating branched-chain amino acid metabolism and energy metabolism. Notably, lactate treatment normalized the levels of eight essential metabolites in DMA mice, underscoring its potential as a therapeutic agent against the consequences of prolonged inactivity and muscle wasting. This study not only advances our understanding of the therapeutic benefits of lactate but also provides a foundation for novel treatment approaches aimed at metabolic restoration and muscle recovery in conditions of muscle wasting.

Physical inactivity has many detrimental effects on health, yet the impact of physical inactivity in early life on muscle health in adulthood remains unknown. Early postnatal malnutrition has prolonged effects into adulthood and we propose that early postnatal (P) physical inactivity would have similar negative effects. To test this hypothesis, we exposed postnatal mice (∼P28, C57BL/6J) to 14 days of physical inactivity (shortly after weaning, from ∼P28 to P42 days of age) in the form of muscle disuse with hindlimb unloading (HU). After this early-life physical inactivity, they were allowed to normally ambulate until 5 mo of age (P140, adulthood) when they underwent 14 days of HU with and without 7-day recovery. They were then tested for physical function (grip strength) and muscles were extracted and weighed. Immunofluorescence was carried out on these muscle cross sections for analysis of myofiber cross-sectional area (fCSA), macrophage density (CD68+ cells), and extracellular matrix (ECM) area. Muscle weights and fCSA and myofiber diameter were used to quantify changes in muscle and fiber size. Compared with age-matched controls, no notable effects of early-life physical inactivity (HU) on skeletal muscle and myofiber size were observed. However, a significant reduction in adult grip strength was observed in those exposed to HU early in life. This was associated with reduced muscle macrophages and increased ECM area. Exposure to a short period of early life disuse has negative enduring effects into adulthood impacting grip strength, muscle macrophages, and muscle composition as low muscle quality.NEW & NOTEWORTHY We demonstrate that early life disuse resulted in less grip strength in adulthood. Analysis of muscle composition demonstrated no loss of whole muscle or myofiber size indicating lower muscle quality akin to premature aging. This poor muscle quality was characterized by altered muscle macrophages and extracellular matrix area. We demonstrate intriguing correlations between this loss of grip strength and muscle macrophages and also area of noncontractile tissue in the muscle.

The space environment includes unique hazards like radiation and microgravity which can adversely affect biological systems. We assessed a multi-omics NASA GeneLab dataset where mice were hindlimb unloaded and/or gamma irradiated for 21 days followed by retinal analysis at 7 days, 1 month or 4 months post-exposure. We compared time-matched epigenomic and transcriptomic retinal profiles resulting in a total of 4178 differentially methylated loci or regions, and 457 differentially expressed genes. Highest correlation in methylation difference was seen across different conditions at the same time point. Nucleotide metabolism biological processes were enriched in all groups with activation at 1 month and suppression at 7 days and 4 months. Genes and processes related to Notch and Wnt signaling showed alterations 4 months post-exposure. A total of 23 genes showed significant changes in methylation and expression compared to unexposed controls, including genes involved in retinal function and inflammatory response. This multi-omics analysis interrogates the epigenomic and transcriptomic impacts of radiation and hindlimb unloading on the retina in isolation and in combination and highlights important molecular mechanisms at different post-exposure stages.

Existing methods for muscle atrophy evaluation based on muscle size measures from ultrasound images are inadequate in precision. Radiomics has been widely used in various medical studies, but its validity for the evaluation of muscle atrophy has not been fully explored.
This study presents a radiomics analysis for muscle atrophy evaluation using ultrasound images. The hindlimb unloading rat model was developed to simulate weightlessness muscle atrophy and ultrasound images of the hind limbs were acquired for both the hindlimb unloaded (HU) and control groups during a 21-day HU period. A total of 368 radiomics features were extracted and the stable and informative features were selected through a two-stage feature selection procedure. The feature change trajectory of the stable features was analyzed using the hierarchical clustering method. Finally, an adaptive longitudinal feature selection and grading network, ALNet, was developed to evaluate muscle atrophy.
The clustering trajectories of ultrasound image features showed similar trends to the changes in muscle atrophy at the molecular level. The best grading accuracy achieved by the ALNet was 79.5% for the Soleus (Sol) muscle and 82.6% for the Gastrocnemius (Gas) muscle.
The test-retest is essential in performing radiomics analysis on ultrasound images. The longitudinal feature selection is important for muscle atrophy grading. The ultrasound image features of the Gas muscle have better discrimination ability than that of the Sol muscle. This study proves for the first time the capability of ultrasound image features for muscle atrophy evaluation.

A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological significance and mechanisms of such activity of motoneurons under unloading conditions are currently unclear. Since hyperactivity of motoneurons and muscle spasticity after spinal cord injury are associated with KCC2 downregulation, we hypothesized that a decrease in potassium (K+)/chloride (Cl-) co-transporter 2 (KCC2) in motoneurons would be responsible for an increase in soleus muscle EMG activity during HS. We aimed to investigate the effect of prochlorperazine (KCC2 activator) on the electrical activity of rat soleus muscle under HS. Wistar rats were divided into the following groups: (1) vivarium control (C), (2) 7-day HS group (7HS) and (3) 7-day HS group plus intraperitoneal injections of prochlorperazine (10 mg/kg, daily) (7HS + P). Expression of proteins in the motoneurons of the lumbar spinal cord was determined by Western blotting. An electromyogram of the rat soleus muscle was recorded using intramuscular electrodes. KCC2 content after 7-day HS significantly decreased by 34% relative to the control group. HS-induced decrease in KCC2 protein content was prevented by prochlorperazine administration. HS also induced a significant 80% decrease in KCC2 Ser940 phosphorylation; however prochlorperazine did not affect KCC2 phosphorylation. The treatment of the rats with prochlorperazine prevented a HS-induced increase in Na(+)/K(+)/(Cl-) co-transporter 1 (KCC2 antagonist) protein content. In parallel with the restoration of KCC2 content, prochlorperazine administration during HS partially prevented an increase in the soleus muscle tonic EMG activity. Thus, prochlorperazine administration during 7-day HS prevents a decrease in KCC2 protein expression in motoneurons and significantly reduces the level of HS-induced soleus muscle electrical activity.

Even without evidence, rehabilitation practitioners continue to introduce new interventions to enhance the mobility outcomes for the increasing population with a recent total knee arthroplasty (TKA).
To compare post-TKA functional mobility outcomes among 3 newly developed physical therapy protocols with a standard-of-care post-TKA rehabilitation protocol.
This randomized clinical trial included 4 study arms implemented in 15 outpatient clinics within a single health system in the Baltimore, Maryland, and Washington, District of Columbia, region from October 2013 to April 2017. Participants included patients who underwent elective unilateral TKA, were aged 40 years and older, and began outpatient physical therapy within 24 days after TKA. A total of 505 patients were screened and 386 participants were enrolled. Patients provided informed consent and were randomly assigned to 1 of 4 groups. Blinding patients and treating therapists was not feasible owing to the nature of the intervention. Analysis was conducted under the modified intent-to-treat principle from October 2017 to May 2019.
The control group used a standard recumbent bike for 15 to 20 minutes each session. Interventions used 1 of 3 modalities for 15 to 20 minutes each session: (1) a body weight-adjustable treadmill, (2) a patterned electrical neuromuscular stimulation device, or (3) a combination of the treadmill and electrical neuromuscular stimulation.
Outcomes included the Activity Measure for Post-acute Care basic mobility score, a patient-reported outcome measure, and the 6-minute walk test. Outcomes were measured at baseline, monthly, and on discharge from outpatient therapy.
Data from 363 patients (mean [SD] age, 63.4 [7.9] years; 222 [61.2%] women) were included in the final analysis, including 92 participants randomized to the control group, 91 participants randomized to the treadmill group, 90 participants randomized to the neuromuscular stimulation device group, and 90 participants randomized to the combination intervention group. Activity Measure for Post-acute Care scores at discharge were similar across groups, ranging from 61.1 to 61.3 (P = .99) with at least 9.0 points improvement (P = .80) since baseline. The distances as measured by the 6-minute walking test were not statistically different across groups (range, 382.9-404.5 m; P = .60).
This randomized clinical trial found no statistically or clinically significant differences in outcomes across the 4 arms. Because outcomes were similar among arms, clinicians should instead consider relative cost in tailoring TKA rehabilitation.
ClinicalTrials.gov Identifier: NCT02426190.

Armillaria mellea, also known as Hazel mushroom, is a delicious food material and traditional herbal medicine in East Asia. Protoilludane sesquiterpenoid aromatic esters from A. mellea (PSAM) are the main active components with antibacterial and anticancer activities. This study explored the antidepressant-like activities of PSAM and its possible mechanisms of action using the open field test (OFT), tail suspension test (TST) and forced swimming test (FST) in mice for the first time. The results revealed that PSAM (1 mg/kg, i.p.) exhibited markedly antidepressant-like activity, which could be reversed by pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist), NMDA (an agonist at the glutamate site). Meanwhile, PSAM also effectively increased the hippocampus dopamine (DA) and γ-aminobutyric acid (GABA) and decreased the hippocampus glutamate (Glu) levels of mice, indicating that the antidepressant-like effect of PSAM might be mediated by the DAergic, GABAergic and Gluergic systems.

Cerebrovascular accidents (CVAs), commonly known as strokes, can damage the brain through vascular injuries caused by either blood vessel blockages (ischemic stroke) or ruptures (hemorrhagic stroke) which disrupt regular brain blood supply and can cause severe damage to the individual. The objective of the present study was to evaluate the effects of photobiomodulation with a light-emitting diode (LED) device (904 nm, 110 mW, 7 J/cm2) on neurogenesis, muscle resistance, and motor behavior in animals submitted to an experimental model of hemiplegia. The sample consisted of 30 Wistar rats, divided into two groups: control group (GC) and 904-nm LED-treated group (TG). All animals underwent stereotactic surgery for electrode implant and subsequent electrolytic injury to induce an ischemic stroke. TG was subjected to daily LED irradiation (904 nm, 110 mW, 7 J/cm2) for 63 s. Suspension test results indicate an improvement of TG muscle resistance when compared with baseline evaluation (BLT); a reduction in open-field freezing time and the number of fecal bolus pellets suggest diminished anxiety induced by 904-nm LED treatment on treatment days 7 and 21 (TG7 and TG21) compared with the baseline results; and lastly, histological analysis showed important signs of neurogenesis in TG in comparison to CG, especially on treatment days 7 and 21 (TG7 and TG21). In conclusion, the present study suggests that 904-nm LED irradiation may beneficially affect neurogenesis, muscle resistance, and animal motor behavior following ischemic CVA.

Suppressive effects of ginsenoside Rh₂ (Rh₂), (24R)-pseudo-ginsenoside HQ (R-PHQ), and (24S)-pseudo-ginsenoside HQ (S-PHQ) against lipopolysaccharide (LPS)-induced depression-like behavior were evaluated using the forced swimming test (FST) and tail suspension test (TST) in mice. Pretreatment with Rh₂, R-PHQ, and S-PHQ significantly decreased immobility time in FST and TST with clear dose-dependence, and significantly downregulated levels of serum tumor necrosis factor-α and interleukin-6, and upregulated superoxide dismutase activity in the hippocampus of LPS-challenged mice. Furthermore, R-PHQ and S-PHQ significantly increased the expression of the brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), sirtuin type 1 (Sirt1), and nuclear-related factor 2, and inhibited the phosphorylation of inhibitor of κB-α and nuclear factor-κB (NF-κB) in the hippocampus of LPS-challenged mice. Additionally, the antidepressant-like effect of R-PHQ was found related to the dopaminergic (DA), γ-aminobutyric acid (GABA)ergic, and noradrenaline systems, while the antidepressive effect of S-PHQ was involved in the DA and GABAergic systems. Taken together, these results suggested that Rh₂, R-PHQ, and S-PHQ produced significant antidepressant-like effects, which may be related to the BDNF/TrkB and Sirt1/NF-κB signaling pathways.

The paper presents the results of a comparative analysis of the biomechanical characteristics human\'s walking before and after a stay in a long-term head-down bed rest at a -6 degrees angle simulating a microgravity (the HDBR-group) and in head-up bed rest (HUBR) at a +9.6 degrees angle as a analogue of lunar gravity (the HUBR-group). The biomechanical characteristics of the walking on a treadmill pace of 60 steps/minute before and after bed rest were analyzed. We investigated also the electromyographic characteristics of leg muscles and recorded the angles in the following joints: hip joint, knee joint and ankle joint. The most pronounced effect on the parameters of the humans walking was found in the HDBR-group. It was manifested in the changes of angles in the leg joints at various phases of a step change and in an electromyographic activity of muscles. Similar, but less pronounced changes of walking biomechanical characteristics were found after bed rest in the HUBR-group.