Search

Sarcopenia is a systemic medical disorder characterized by a gradual decline in muscular strength, function, and skeletal muscle mass. Currently, there is no medication specifically approved for the treatment of this condition. Therefore, the identification of new pharmacological targets may offer opportunities for the development of novel therapeutic strategies. The current in silico study investigated the active ingredients and the mode of action of Citri Reticulatae Pericarpium (CRP) in addressing sarcopenia. The active ingredients of CRP and the potential targets of CRP and sarcopenia were determined using various databases. The STRING platform was utilized to construct a protein–protein interaction network, and the key intersecting targets were enriched through the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Molecular docking was used to determine the binding interactions of the active ingredients with the hub targets. The binding affinities obtained from molecular docking were subsequently validated through molecular dynamics simulation analyses. Five active ingredients and 45 key intersecting targets between CRP and sarcopenia were identified. AKT1, IL6, TP53, MMP9, ESR1, NFKB1, MTOR, IGF1R, ALB, and NFE2L2 were identified as the hub targets with the highest degree node in the protein–protein interaction network. The results indicated that the targets were mainly enriched in PIK3-AKT, HIF-1, and longevity-regulating pathways. The active ingredients showed a greater interaction affinity with the hub targets, as indicated by the results of molecular docking and molecular dynamics simulations. Our findings suggest that the active ingredients of Citri Reticulatae Pericarpium, particularly Sitosterol and Hesperetin, have the potential to improve sarcopenia by interacting with AKT1 and MTOR proteins through the PI3K-AKT signaling pathway. [ABSTRACT FROM AUTHOR]

As we age, we lose muscle strength and power, a condition commonly referred to as sarcopenia (ICD-10-CM code (M62.84)). The prevalence of sarcopenia is about 5–10% of the elderly population, resulting in varying degrees of disability. In this review we emphasise that sarcopenia does not occur suddenly. It is an aging-induced deterioration that occurs over time and is only recognised as a disease when it manifests clinically in the 6th–7th decade of life. Evidence from animal studies, elite athletes and longitudinal population studies all confirms that the underlying process has been ongoing for decades once sarcopenia has manifested. We present hypotheses about the mechanism(s) underlying this process and their supporting evidence. We briefly review various proposals to impede sarcopenia, including cell therapy, reducing senescent cells and their secretome, utilising targets revealed by the skeletal muscle secretome, and muscle innervation. We conclude that although there are potential candidates and ongoing preclinical and clinical trials with drug treatments, the only evidence-based intervention today for humans is exercise. We present different exercise programmes and discuss to what extent the interindividual susceptibility to developing sarcopenia is due to our genetic predisposition or lifestyle factors. [ABSTRACT FROM AUTHOR]

The gradual deterioration of physiological systems with ageing makes it difficult to maintain skeletal muscle mass (sarcopenia), at least partly due to the presence of 'anabolic resistance', resulting in muscle loss. Sarcopenia can be transiently but markedly accelerated through periods of muscle disuse‐induced (i.e., unloading) atrophy due to reduced physical activity, sickness, immobilisation or hospitalisation. Periods of disuse are detrimental to older adults' overall quality of life and substantially increase their risk of falls, physical and social dependence, and early mortality. Disuse events induce skeletal muscle atrophy through various mechanisms, including anabolic resistance, inflammation, disturbed proteostasis and mitochondrial dysfunction, all of which tip the scales in favour of a negative net protein balance and subsequent muscle loss. Concerningly, recovery from disuse atrophy is more difficult for older adults than their younger counterparts. Resistance training (RT) is a potent anabolic stimulus that can robustly stimulate muscle protein synthesis and mitigate muscle losses in older adults when implemented before, during and following unloading. RT may take the form of traditional weightlifting‐focused RT, bodyweight training and lower‐ and higher‐load RT. When combined with sufficient dietary protein, RT can accelerate older adults' recovery from a disuse event, mitigate frailty and improve mobility; however, few older adults regularly participate in RT. A feasible and practical approach to improving the accessibility and acceptability of RT is through the use of resistance bands. Moving forward, RT must be prescribed to older adults to mitigate the negative consequences of disuse atrophy. What is the topic of this review?Use of resistance exercise training to prevent or mitigate the disuse‐induced muscle atrophy in an ageing population.What advances does it highlight?The review highlights several potential mechanisms of disuse‐induced muscle atrophy and strategies before, during and following disuse to prevent, mitigate and recover lost muscle. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a progressive disorder associated with a decline in kidney function. Consequently, patients with advanced stages of CKD require renal replacement therapies, such as dialysis and kidney transplantation. Various conditions lead to the development of CKD, including diabetes mellitus, hypertension, and glomerulonephritis, among others. The disease is associated with metabolic and hormonal dysregulation, including uraemia and hyperparathyroidism, as well as with low-grade systemic inflammation. Altered homeostasis increases the risk of developing severe comorbidities, such as cardiovascular diseases or sarcopenia, which increase mortality. Sarcopenia is defined as a progressive decline in muscle mass and function. However, the precise mechanisms that link CKD and the development of sarcopenia are poorly understood. Knowledge about these linking mechanisms might lead to the introduction of precise treatment strategies that could prevent muscle wasting. This review discusses inflammatory mediators, metabolic and hormonal dysregulation, gut microbiota dysbiosis, and non-coding RNA alterations that could link CKD and sarcopenia. [ABSTRACT FROM AUTHOR]

Periods of skeletal muscle disuse lead to rapid declines in muscle mass (atrophy), which is fundamentally underpinned by an imbalance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). The complex interplay of molecular mechanisms contributing to the altered regulation of muscle protein balance during disuse have been investigated but rarely synthesised in the context of humans. This narrative review discusses human models of muscle disuse and the ensuing inversely exponential rate of muscle atrophy. The molecular processes contributing to altered protein balance are explored, with a particular focus on growth and breakdown signalling pathways, mitochondrial adaptations and neuromuscular dysfunction. Finally, key research gaps within the disuse atrophy literature are highlighted providing future avenues to enhance our mechanistic understanding of human disuse atrophy. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria. [ABSTRACT FROM AUTHOR]

Background: The study aimed to examine the bidirectional relationship between sarcopenia and depressive symptoms in a national, community-based cohort study, despite the unclear temporal sequence demonstrated previously. Methods: Data were derived from four waves (2011 baseline and 2013, 2015, and 2018 follow-ups) of the China Health and Retirement Longitudinal Study (CHARLS). A total of 17,708 participants aged 45 years or older who had baseline data on both sarcopenia status and depressive symptoms in 2011 were included in the study. For the two cohort analyses, a total of 8092 adults without depressive symptoms and 11,292 participants without sarcopenia in 2011 were included. Sarcopenia status was defined according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. Depressive symptoms were defined as a score of 20 or higher on the 10-item Center for Epidemiologic Studies Depressive Scale (CES-D-10). Cox proportional hazard regression models were conducted to examine the risk of depressive symptoms and sarcopenia risk, while cross-lagged panel models were used to examine the temporal sequence between depressive symptoms and sarcopenia over time. Results: During a total of 48,305.1 person-years follow-up, 1262 cases of incident depressive symptoms were identified. Sarcopenia exhibited a dose–response relationship with a higher risk of depressive symptoms (HR = 1.7, 95%CI: 1.2–2.3 for sarcopenia, and HR = 1.5, 95%CI: 1.2–1.8 for possible sarcopenia, p trend < 0.001). In the second cohort analysis, 240 incident sarcopenia cases were identified over 39,621.1 person-years. Depressive symptoms (HR = 1.5, 95%CI: 1.2–2.0) are significantly associated with a higher risk of developing sarcopenia after multivariable adjustment (p < 0.001, Cross-lagged panel analyses demonstrated that depressive symptoms were associated with subsequent sarcopenia (β = 0.003, p < 0.001). Simultaneously, baseline sarcopenia was also associated with subsequent depressive symptoms (β = 0.428, p < 0.001). Conclusion: This study identified a bidirectional relationship between depressive symptoms and sarcopenia. It seems more probable that baseline sarcopenia is associated with subsequent depressive symptoms in a stronger pattern than the reverse pathway. The interlinkage indicated that maintaining normal muscle mass and strength may serve as a crucial intervention strategy for alleviating mood disorders. [ABSTRACT FROM AUTHOR]

Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia–reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia. [ABSTRACT FROM AUTHOR]

Sarcopenia, the age-associated decline in skeletal muscle mass and strength, is a condition with a complex pathophysiology. Among the factors underlying the development of sarcopenia are the progressive demise of motor neurons, the transition from fast to slow myosin isoform (type II to type I fiber switch), and the decrease in satellite cell number and function. Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging. Several systems have been implicated in the regulation of muscle plasticity and trophism such as the fine-tuned and complex regulation between the stimulator of protein synthesis, mechanistic target of rapamycin (mTOR), and the inhibitor of mTOR, AMP-activated protein kinase (AMPK), that promotes muscle catabolism. Here, we provide an overview of the molecular mechanisms linking mitochondrial signaling and quality with muscle homeostasis and performance and discuss the main pathways elicited by their imbalance during age-related muscle wasting. We also discuss lifestyle interventions (i.e., physical exercise and nutrition) that may be exploited to preserve mitochondrial function in the aged muscle. Finally, we illustrate the emerging possibility of rescuing muscle tissue homeostasis through mitochondrial transplantation. [ABSTRACT FROM AUTHOR]

This study is focused on the fact that in the context of increasing global aging and cancer diagnoses, additional challenges arise in clinical care. Adequate functionality and body composition are key to coping with antineoplastic treatment, which can lead to better treatment tolerance, survival, and quality of life. This is a cross-sectional comparative study focused on the assessment and comparison of body composition and functionality between cancer patients and a reference population, with the aim of establishing meaningful baseline values. Techniques such as manual dynamometry, the Five-Times Sit-to-Stand test, and bioimpedance were used to collect data from 374 oncologic patients and 1244 reference individuals. The results reveal significant disparities in functionality and body composition among participants, and provide age group-specific adjusted baseline values for those diagnosed with cancer. These findings may have crucial clinical implications for applying particular cut-off points designed for this population group, which makes the assessment process faster and more accurate, enhances the capacity of medical personnel to act quickly, and improves the management of frailty in cancer patients. [ABSTRACT FROM AUTHOR]

Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age‐associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit‐acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia. [ABSTRACT FROM AUTHOR]

Skeletal muscles underpin myriad human activities, maintaining an intricate balance between protein synthesis and degradation crucial to muscle mass preservation. Historically, disruptions in this balance--where degradation overshadows synthesis--have marked the onset of muscle atrophy, a condition diminishing life quality and, in grave instances, imperiling life itself. While multiple protein degradation pathways exist--including the autophagy-lysosome, calcium-dependent calpain, and cysteine aspartate protease systems--the ubiquitin-proteasome pathway emerges as an especially cardinal avenue for intracellular protein degradation, wielding pronounced influence over the muscle atrophy trajectory. This paper ventures a panoramic view of predominant muscle atrophy types, accentuating the ubiquitin-proteasome pathway's role therein. Furthermore, by drawing from recent scholarly advancements, we draw associations between the ubiquitin-proteasome pathway and specific pathological conditions linked to muscle atrophy. Our exploration seeks to shed light on the ubiquitin-proteasome pathway's significance in skeletal muscle dynamics, aiming to pave the way for innovative therapeutic strategies against muscle atrophy and affiliated muscle disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Much of what we know about the loss of skeletal muscle strength and mass (sarcopenia) in old age comes from studies of small laboratory rodents. In humans, this condition is generally not noticeable until late middle age when it affects our mobility (clinical stage). As muscle wasting progresses with age, it poses a challenge to independent living and worsens the health of those of us already suffering from other diseases. WHO and national health authorities have identified sarcopenia as one of the major age-related diseases we must try to curb. Observations in humans show that the process underlying sarcopenia goes on for decades before we notice it (preclinical phase). In this study, we show that the same disease process is observed in rats as in humans, and that skeletal muscles exhibit a series of adaptive responses to maintain muscle function and mass during the long period that precedes clinical symptoms. When these adaptive mechanisms are exhausted, the disease progresses to a clinical stage. We conclude that the rat is a useful model to further study the triggering mechanisms of this disease and, moreover, is suitable for assessing whether interventions to treat the disease are more successful in the preclinical phase than in the clinical phase. The facultative loss of muscle mass and function during aging (sarcopenia) poses a serious threat to our independence and health. When activities of daily living are impaired (clinical phase), it appears that the processes leading to sarcopenia have been ongoing in humans for decades (preclinical phase). Here, we examined the natural history of sarcopenia in male outbred rats to compare the occurrence of motor behavioral deficits with the degree of muscle wasting and to explore the muscle-associated processes of the preclinical and clinical phases, respectively. Selected metrics were validated in female rats. We used the soleus muscle because of its long duty cycles and its importance in postural control. Results show that gait and coordination remain intact through middle age (40–60% of median lifespan) when muscle mass is largely preserved relative to body weight. However, the muscle shows numerous signs of remodeling with a shift in myofiber-type composition toward type I. As fiber-type prevalence shifted, fiber-type clustering also increased. The number of hybrid fibers, myofibers with central nuclei, and fibers expressing embryonic myosin increased from being barely detectable to a significant number (5–10%) at late middle age. In parallel, TGFβ1, Smad3, FBXO32, and MuRF1 mRNAs increased. In early (25-month-old) and advanced (30-month-old) aging, gait and coordination deteriorate with the progressive loss of muscle mass. In late middle age and early aging due to type II atrophy (>50%) followed by type I atrophy (>50%), the number of myofibers did not correlate with this process. In advanced age, atrophy is accompanied by a decrease in SCs and βCatenin mRNA, whereas several previously upregulated transcripts were downregulated. The re-expression of embryonic myosin in myofibers and the upregulation of mRNAs encoding the γ-subunit of the nicotinic acetylcholine receptor, the neuronal cell adhesion molecule, and myogenin that begins in late middle age suggest that one mechanism driving sarcopenia is the disruption of neuromuscular connectivity. We conclude that sarcopenia in rats, as in humans, has a long preclinical phase in which muscle undergoes extensive remodeling to maintain muscle mass and function. At later time points, these adaptive mechanisms fail, and sarcopenia becomes clinically manifest. [ABSTRACT FROM AUTHOR]

Aim: Sarcopenia is defined as the loss of muscle mass and muscle strength, and its frequency increases in kidney patients. However, sarcopenia frequency in patients with glomerulonephritis is unknown. The present study aimed to investigate the frequency of sarcopenia in patients with glomerulonephritis and compare the results with the healthy population for the first time in the literature. Patients and Methods: A total of 110 participants, including 70 patients previously diagnosed with glomerulonephritis and 40 healthy individuals, were included in the study. The diagnosis of sarcopenia was made based on the EWSGOP 2 Criteria. Results: The mean age of the glomerulonephritis patients group was 39.3 ± 1.5. In the anthropometric measurements of the patients, walking speed was low in 50 patients (71.4%), muscle strength was decreased in 44 patients (62.9%), and sarcopenia was detected in 10 patients (14.3%) according to the EWGSOP 2 Criteria. Considering the anthropometric measurements of the control group, sarcopenia was not detected in any of the subjects according to the EWGSOP 2 Criteria. Conclusion: The result of the present study revealed that the rate of sarcopenia was significantly higher in glomerulonephritis patients compared to the healthy population and that sarcopenia can also be observed even in middle age in this population. We think it would be beneficial for clinicians treating glomerulonephritis to be more careful regarding sarcopenia and keep these parameters in mind during treatment. [ABSTRACT FROM AUTHOR]

Microgravity exposure causes several physiological and psychosocial alterations that challenge astronauts' health during space flight. Notably, many of these changes are mostly related to physical inactivity influencing different functional systems and organ biology, in particular the musculoskeletal system, dramatically resulting in aging-like phenotypes, such as those occurring in older persons on Earth. In this sense, sarcopenia, a syndrome characterized by the loss in muscle mass and strength due to skeletal muscle unloading, is undoubtedly one of the most critical aging-like adverse effects of microgravity and a prevalent problem in the geriatric population, still awaiting effective countermeasures. Therefore, there is an urgent demand to identify clinically relevant biological markers and to underline molecular mechanisms behind these effects that are still poorly understood. From this perspective, a lesson from Geroscience may help tailor interventions to counteract the adverse effects of microgravity. For instance, decades of studies in the field have demonstrated that in the older people, the clinical picture of sarcopenia remarkably overlaps (from a clinical and biological point of view) with that of frailty, primarily when referred to the physical function domain. Based on this premise, here we provide a deeper understanding of the biological mechanisms of sarcopenia and frailty, which in aging are often considered together, and how these converge with those observed in astronauts after space flight. [ABSTRACT FROM AUTHOR]

Disuse atrophy, caused by situations of unloading such as limb immobilisation, causes a rapid yet diverging reduction in skeletal muscle function when compared to muscle mass. While mechanistic insight into the loss of mass is well studied, deterioration of muscle function with a focus towards the neural input to muscle remains underexplored. This study aimed to determine the role of motor unit adaptation in disuse‐induced neuromuscular deficits. Ten young, healthy male volunteers underwent 15 days of unilateral lower limb immobilisation with intramuscular electromyography (iEMG) bilaterally recorded from the vastus lateralis (VL) during knee extensor contractions normalised to maximal voluntary contraction (MVC), pre and post disuse. Muscle cross‐sectional area was determined by ultrasound. Individual MUs were sampled and analysed for changes in motor unit (MU) discharge and MU potential (MUP) characteristics. VL CSA was reduced by approximately 15% which was exceeded by a two‐fold decrease of 31% in muscle strength in the immobilised limb, with no change in either parameter in the non‐immobilised limb. Parameters of MUP size were reduced by 11% to 24% with immobilisation, while neuromuscular junction (NMJ) transmission instability remained unchanged, and MU firing rate decreased by 8% to 11% at several contraction levels. All adaptations were observed in the immobilised limb only. These findings highlight impaired neural input following immobilisation reflected by suppressed MU firing rate which may underpin the disproportionate reductions of strength relative to muscle size. Key points: Muscle mass and function decline rapidly in situations of disuse such as bed rest and limb immobilisation.The reduction in muscle function commonly exceeds that of muscle mass, which may be associated with the dysregulation of neural input to muscle.We have used intramuscular electromyography to sample individual motor unit and near fibre potentials from the vastus lateralis following 15 days of unilateral limb immobilisation. Following disuse, the disproportionate loss of muscle strength when compared to size coincided with suppressed motor unit firing rate.These motor unit adaptations were observed at multiple contraction levels and in the immobilised limb only. Our findings demonstrate neural dysregulation as a key component of functional loss following muscle disuse in humans. [ABSTRACT FROM AUTHOR]

Due to the multifactorial pathogenesis of sarcopenia, it is crucial to identify biomarkers that are risk factors for sarcopenia, and which therefore have a prognostic function. Aim: This narrative review aims to define a set of biomarkers associated with nutrition and sarcopenia. These biomarkers could contribute to individualized monitoring and enable preventive and therapeutic methods. Methods: Two electronic databases, PubMed and Google Scholar, were used. The search strategy was based on a controlled vocabulary (MeSH) and includes studies published up to February 2022. Discussion: Higher levels of serum uric acid are associated with higher handgrip strength and better muscle function in elderly people and, thus, may slow the progression of sarcopenia. Leptin, an adipokine secreted by adipose tissue, promotes the production of pro-inflammatory cytokines, which in turn lead to sarcopenia. This makes leptin a significant indirect biomarker for physical disability and sarcopenic obesity. Additionally, creatinine is a reliable biomarker for muscle mass status because of its easy accessibility and cost-effectiveness. Vitamin D status acts as a useful biomarker for predicting total mortality, hip fractures, early death, and the development of sarcopenia. Therefore, there is an increasing interest in dietary antioxidants and their effects on age-related losses of muscle mass and function. On the other hand, 3-Methylhistidine is a valuable biomarker for detecting increased muscle catabolism, as it is excreted through urine during muscle degradation. In addition, IGF-1, whose concentration in plasma is stimulated by food intake, is associated with the loss of skeletal muscle mass, which probably plays a crucial role in the progression of sarcopenia. Conclusions: Many nutritional biomarkers were found to be associated with sarcopenia, and can therefore be used as prognostic indexes and risk factors. Nutrition plays an important role in the prevention and management of sarcopenia, affecting muscle mass, strength, and function in elderly people. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is an essential treatment to combat solid tumours and mitigate metastasis. Chemotherapy causes side effects including muscle wasting and weakness. Regulated in Development and DNA Damage Response 1 (REDD1) is a stress‐response protein that represses the mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), and its expression is increased in models of muscle wasting. The aim of this study was to determine if deletion of REDD1 is sufficient to attenuate chemotherapy‐induced muscle wasting and weakness in mice. Methods: C2C12 myotubes were treated with carboplatin, and changes in myotube diameter were measured. Protein synthesis was measured by puromycin incorporation, and REDD1 mRNA and protein expression were analysed in myotubes treated with carboplatin. Markers of mTORC1 signalling were measured by western blot. REDD1 global knockout mice and wild‐type mice were treated with a single dose of carboplatin and euthanized 7 days later. Body weight, hindlimb muscle weights, forelimb grip strength, and extensor digitorum longus whole muscle contractility were measured in all groups. Thirty minutes prior to euthanasia, mice were injected with puromycin to measure puromycin incorporation in skeletal muscle. Results: C2C12 myotube diameter was decreased at 24 (P = 0.0002) and 48 h (P < 0.0001) after carboplatin treatment. Puromycin incorporation was decreased in myotubes treated with carboplatin for 24 (P = 0.0068) and 48 h (P = 0.0008). REDD1 mRNA and protein expression were increased with carboplatin treatment (P = 0.0267 and P = 0.0015, respectively), and this was accompanied by decreased phosphorylation of Akt T308 (P < 0.0001) and S473 (P = 0.0006), p70S6K T389 (P = 0.0002), and 4E‐binding protein 1 S65 (P = 0.0341), all markers of mTORC1 activity. REDD1 mRNA expression was increased in muscles from mice treated with carboplatin (P = 0.0295). Loss of REDD1 reduced carboplatin‐induced body weight loss (P = 0.0013) and prevented muscle atrophy in mice. REDD1 deletion prevented carboplatin‐induced decrease of protein synthesis (P = 0.7626) and prevented muscle weakness. Conclusions: Carboplatin caused loss of body weight, muscle atrophy, muscle weakness, and inhibition of protein synthesis. Loss of REDD1 attenuates muscle atrophy and weakness in mice treated with carboplatin. Our study illustrates the importance of REDD1 in the regulation of muscle mass with chemotherapy treatment and may be an attractive therapeutic target to combat cachexia. [ABSTRACT FROM AUTHOR]

Background: Ghrelin may ameliorate cancer cachexia (CC) by preventing anorexia, muscle, and fat loss. However, the mechanisms mediating these effects are not fully understood. This study characterizes the pathways involved in muscle mass and strength loss in the Lewis lung carcinoma (LLC)‐induced cachexia model, and the effects of ghrelin in mice with or without its only known receptor: the growth hormone secretagogue receptor‐1a ((GHSR‐1a), Ghsr+/+ and Ghsr−/−). Methods: Five to 7‐month‐old male C57BL/6J Ghsr+/+ and Ghsr−/− mice were inoculated with 1 × 106 heat‐killed (HK) or live LLC cells (tumour implantation, TI). When tumours were palpable (7 days after TI), tumour‐bearing mice were injected with vehicle (T + V) or ghrelin twice/day for 14 days (T + G, 0.8 mg/kg), while HK‐treated mice were given vehicle (HK + V). Body weight and grip strength were evaluated before TI and at termination (21 days after TI). Hindlimb muscles were collected for analysis. Results: Less pronounced body weight (BW) loss (87.70 ± 0.98% vs. 83.92 ± 1.23%, percentage of baseline BW in tumour‐bearing Ghsr+/+ vs. Ghsr−/−, P = 0.008), and lower upregulation of ubiquitin‐proteasome system (UPS, MuRF1/Trim63, 5.71 ± 1.53‐fold vs. 9.22 ± 1.94‐fold‐change from Ghsr+/+ HK + V in tumour‐bearing Ghsr+/+ vs. Ghsr‐/‐, P = 0.036) and autophagy markers (Becn1, Atg5, Atg7, tumour‐bearing Ghsr+/+ < Ghsr−/−, all P < 0.02) were found in T + V Ghsr+/+ vs. Ghsr−/− mice. Ghrelin attenuated LLC‐induced UPS marker upregulation in both genotypes, [Trim63 was decreased from 5.71 ± 1.53‐fold to 1.96 ± 0.47‐fold in Ghsr+/+ (T + V vs. T + G: P = 0.032) and 9.22 ± 1.94‐fold to 4.72 ± 1.06‐fold in Ghsr−/− (T + V vs. T + G: P = 0.008)]. Only in Ghsr+/+ mice ghrelin ameliorated LLC‐induced grip strength loss [improved from 89.24 ± 3.48% to 97.80 ± 2.31% of baseline (T + V vs. T + G: P = 0.042)], mitophagy markers [Bnip3 was decreased from 2.28 ± 0.56 to 1.38 ± 0.14‐fold (T + V vs. T + G: P ≤ 0.05)], and impaired mitochondrial respiration [State 3u improved from 698.23 ± 73.96 to 934.37 ± 95.21 pmol/min (T + V vs. T + G: P ≤ 0.05)], whereas these markers were not improved by ghrelin Ghsr−/−. Compared with Ghsr+/+, Ghsr−/− tumour‐bearing mice also showed decreased response to ghrelin in BW [T + G‐treated Ghsr+/+ vs. Ghsr−/−: 91.75 ± 1.05% vs. 86.18 ± 1.13% of baseline BW, P < 0.001)], gastrocnemius (T + G‐treated Ghsr+/+ vs. Ghsr−/−: 96.9 ± 2.08% vs. 88.15 ± 1.78% of Ghsr+/+ HK + V, P < 0.001) and quadriceps muscle mass (T + G‐treated Ghsr+/+ vs. Ghsr−/−: 96.12 ± 2.31% vs. 88.36 ± 1.94% of Ghsr+/+ HK + V, P = 0.01), and gastrocnemius type IIA (T + G‐treated Ghsr+/+ vs. Ghsr−/−: 1250.49 ± 31.72 vs. 1017.62 ± 70.99 μm2, P = 0.027) and IIB fibre cross‐sectional area (T + G‐treated Ghsr+/+ vs. Ghsr−/−: 2496.48 ± 116.88 vs. 2183.04 ± 103.43 μm2, P = 0.024). Conclusions: Growth hormone secretagogue receptor‐1a mediates ghrelin's effects on attenuating LLC‐induced weakness but not muscle mass loss by modulating the autophagy‐lysosome pathway, mitophagy, and mitochondrial respiration. [ABSTRACT FROM AUTHOR]

Motor Unit conduction velocity (MUCV) relates to muscle fiber diameter and is considered a size principle parameters.1,2 In the present study, the MUCV response to 10 days of unilateral limb suspension (ULLS), was investigated using high-density surface electromyography (HDsEMG). In addition, muscle biopsies were collected. All measures were performed at baseline (LS0) and after the ULLS (LS10). Ten healthy young male volunteers underwent, over two sessions, HDsEMG recording during trapezoidal isometric contractions at 25 and 50% of maximal voluntary contraction (MVC) using a 64 electrodes grid positioned over the vastus lateralis muscle. MUCV and action potential amplitude were computed at recruitment on the double differential derivation of MUs action potential waveforms along the electrode columns as previously described2. MUs action potential amplitude was calculated as the root mean square of the waveforms (RMS) on the same channels used for MUCV calculation. Muscle fibre diameter was estimated from serial cross-sections stained for myofibrillar ATPase. Correlations between MUCV and muscle fiber diameter were computed at LS0 and LS10 and were reported as coefficient of determination (R2). Preliminary results for a subgroup of 7 participants out of 10 showed decreased MUCV at LS10 from 4.40 ± 0.13 m/s to 4.07 ± 0.13 m/s at 25% MVC (p<0.001) and from 4.64 ± 0.13 to 4.30 ± 0.14 m/s at 50% MVC (p<0.001). MUs RMS was not affected by the intervention (from 41.70 ± 7.13 to 44.70 ± 7.17 mV at 25% MVC (p=0.269) and from 59.10 ± 8.06 to 66.50 ± 8.60 mV at 50% MVC(p=0.119)). MUCV showed a strong correlation with muscle fibers diameter at LS0 (R2=0.78 at 25% MVC and R2=0.64 at 50% MVC). However, this correlation was disrupted by the intervention (at LS10, R2=0.22 at 25% MVC and R2=0.30 at 50% MVC). This last finding suggests that other non-structural factors, such as ion channels dysregulation (e.g., calcium handling), could be responsible for the observed reduction in MUCV and lack of correlation between MUCV and estimated fiber diameter after 10 days of unilateral limb suspension. [ABSTRACT FROM AUTHOR]

Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function. [ABSTRACT FROM AUTHOR]