Preserve Muscle Function Research Articles

Assessment of myosteatosis and functionality in pretreatment gynecological cancer patients.

We aimed to investigate the relationship between pretreatment gynecologic cancer survival and the physical function of patients with myosteatosis. Understanding this relationship prior to treatment would help healthcare providers identify and refer patients with poor muscle quality to an exercise program prior to treatment. We conducted a cross-sectional analysis of 73 GC patients. Physical function was quantified using handgrip strength and an adapted version of the Senior Fitness Test (aerobic endurance not included). The EORTC QLC-C30 was used to evaluate general health quality. Myosteatosis (values below the median muscle radiodensity), muscle mass, and adipose tissue variables were calculated from the computed tomography (CT) scan at the third lumbar vertebra using specific software. Seventy patients (50.9 ± 15.2) were included; 41.5% had stage III or IV disease, and 61.4% had cervical cancer. The myosteatosis group was 11.9years older and showed reduced functioning compared to the normal-radiodensity group. Age and Timed Up and Go (TUG) test results were shown to be the most reliable predictors of muscle radiodensity in pretreatment gynecological patients according to multivariate regression analysis (R2 = 0.314). Gynecological healthcare professionals should be aware that prompt exercise programs might be especially beneficial for older patients with reduced TUG performance to preserve muscle function and quality.

Cerium Oxide Nanozymes Improve Skeletal Muscle Function in Gestational Diabetic Offspring by Attenuating Mitochondrial Oxidative Stress.

Gestational diabetes mellitus (GDM) is a significant complication during pregnancy that results in abnormalities in the function of multiple systems in the offspring, which include skeletal muscle dysfunction and reduced systemic metabolic capacity. One of the primary causes behind this intergenerational effect is the presence of mitochondrial dysfunction and oxidative stress in the skeletal muscle of the offspring due to exposure to a high-glucose environment in utero. Cerium oxide (CeO2) nanozymes are antioxidant agents with polymerase activity that have been widely used in the treatment of inflammatory and aging diseases. In this study, we synthesized ultrasmall particle size CeO2 nanozymes and applied them in GDM mouse offspring. The CeO2 nanozymes demonstrated an ability to increase insulin sensitivity and enhance skeletal muscle motility in GDM offspring by improving mitochondrial activity, increasing mitochondrial ATP synthesis function, and restoring abnormal mitochondrial morphology. Furthermore, at the cellular level, CeO2 nanozymes could ameliorate metabolic dysregulation and decrease cell differentiation in adult muscle cells induced by hyperglycemic stimuli. This was achieved through the elimination of endogenous reactive oxygen species (ROS) and an improvement in mitochondrial oxidative respiration function. In conclusion, CeO2 nanozymes play a crucial role in preserving muscle function and maintaining the metabolic stability of organisms. Consequently, they serve to reverse the negative effects of GDM on skeletal muscle physiology in the offspring.

Expression of the TGF-β Target Gene Mss51 Is Induced in Muscle From Tumor-Bearing Mice and Attenuated by Treatment With the AMPK Activator AICAR

Cachexia is a severe complication of cancer characterized by skeletal muscle atrophy and loss of function and is associated with a poor prognosis. AMPK is a cellular energy sensor that is upregulated in cancer cachexia. AMPK activation is well-established in promoting catabolic cell signaling in skeletal muscle, partly through the induction of muscle-specific ubiquitin ligases MAFBx and MuRF-1 expression. Despite AMPK’s acute catabolic effects, chronic treatment with the AMPK-activating drug 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) has been reported to preserve muscle function and metabolism in various muscle-wasting conditions, including cancer cachexia. Elevated TGF-β during cancer cachexia is known to disrupt mitochondrial homeostasis and lead to mitochondrial dysfunction. Mss51 is a skeletal muscle-specific mitochondrial gene that is upregulated through TGF-β signaling. Although the role of Mss51 in skeletal muscle cancer cachexia has not been studied as of yet, its expression is associated with mitochondrial and metabolic impairment. Therefore, we hypothesized that Mss-51 expression would be elevated in cachexic skeletal muscle and attenuated by chronic AMPK activation. To test this, we inoculated mice (n=4) with either Lewis Lung Carcinoma (LLC) cells or PBS. Mice were injected daily with 350 mg/kg AICAR or an equivalent volume of saline beginning seven days after inoculation. Twenty-four days after inoculation, the mice were euthanized, and tissues were harvested and weighed. RNA was isolated from the gastrocnemius-plantaris-soleus complex and analyzed by RT-PCR for Mss51, MuRF-1, and MAFBx expression. Protein expression for hexokinase II (HKII) was measured by western blotting. AICAR treatment did not attenuate muscle atrophy in tumor-bearing mice. Compared to the control, Mss-51 was elevated in LLC mice treated with saline and decreased in LLC mice treated with AICAR, consistent with the known effects of AMPK in blocking TGF-β signaling. Similarly, MuRF-1 and MAFBx tended to be elevated in LLC-saline. Still, this increase was attenuated in LLC-AICAR mice, though we were likely underpowered to detect significance in this measure. In conclusion, based on previous work, the rise in Mss51 in tumor-bearing mice may contribute to mitochondrial and metabolic dysfunction in cancer cachexia. The prevention of this increase by AICAR suggests that AMPK may benefit dysfunctional metabolism in the cachexic muscle through inhibition of Mss51. Funding for these experiments was from a BYU Widtsoe Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Effects of Acute Deep Seawater Supplementation on Muscle Function after Triathlon.

(1) Background: Trainers and athletes have always sought to reduce the failure of muscle function during long endurance events. However, nowadays, it is a topic that is generating much debate in the scientific field. Currently, deep-sea water (DSW) intake seems to be a suitable hydration alternative for this type of endurance event. Therefore, the aim of this study was to determine whether DSW consumption during a triathlon event could preserve muscle function after exercise. (2) Methods: Nineteen trained male triathletes (age = 39.0 ± 4.25 years; BMI = 23.67 ± 1.81 kg/m2) randomly performed three triathlons, one of them consuming DSW (Totum SPORT 30 AB, Laboratories Quinton International, S.L., Spain), the other consuming isotonic placebo and the last with tap water-hydration. A vertical jump test with countermovement and an isometric muscle strength test were conducted before and after the triathlon test. (3) Results: There was a significant difference between treatment × time during the isometric muscle strength test. Based on the Tukey post hoc analysis, the peak net force decreased statistically in the placebo (p = 0.045) and control conditions (p = 0.026), but not in the experimental condition (p = 0.121). In addition, all of the conditions studied obtained similar results in the countermovement vertical jump after exercise. (4) Conclusions: As a result, consumption of DSW seems to delay the failure of muscle function specifically in isometric exercises but does not improve performance in sports. Thus, DSW does not alter muscle capacity in a negative way; therefore, its consumption may be recommended.

Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies.

Sarcopenia is a multifactorial condition characterized by loss of muscle mass. It poses significant health risks in older adults worldwide. Both pharmacological and non-pharmacological approaches are reported to address this disease. Certain dietary patterns, such as adequate energy intake and essential amino acids, have shown positive outcomes in preserving muscle function. Various medications, including myostatin inhibitors, growth hormones, and activin type II receptor inhibitors, have been evaluated for their effectiveness in managing sarcopenia. However, it is important to consider the variable efficacy and potential side effects associated with these treatments. There are currently no drugs approved by the Food and Drug Administration for sarcopenia. The ongoing research aims to develop more effective strategies in the future. Our review of research on disease mechanisms and drug development will be a valuable contribution to future research endeavors.

Effects of C-Peptide on Dexamethasone-Induced In Vitro and In Vivo Models as a Potential Therapeutic Agent for Muscle Atrophy.

This study aimed to investigate the effects of C-peptide on C2C12 myotubes and a mouse model. Both in vitro and in vivo experiments were conducted to elucidate the role of C-peptide in muscle atrophy. Various concentrations (0, 0.01, 0.1, 1, 10, and 100 nM) of C-peptide were used on the differentiated C2C12 myotubes with or without dexamethasone (DEX). C57BL/6J mice were administered with C-peptide and DEX for 8 days, followed by C-peptide treatment for 12 days. Compared to the DEX group, C-peptide increased the fusion and differentiation indices and suppressed atrophic factor expression in C2C12 myotubes. However, 100 nM C-peptide decreased the fusion and differentiation indices and increased atrophic factor expression regardless of DEX treatment. In C57BL/6J mice, DEX + C-peptide co-treatment significantly attenuated the body and muscle weight loss and improved the grip strength and cross-sectional area of the gastrocnemius (Gas) and quadriceps (Quad) muscles. C-peptide downregulated the mRNA and protein levels of muscle degradation-related markers, particularly Atrogin-1, in Gas and Quad muscles. This study underscores the potential of C-peptides in mitigating muscle weight reduction and preserving muscle function during muscle atrophy via molecular regulation. In addition, the work presents basic data for future studies on the effect of C-peptide on diabetic muscular dystrophy.

Carbohydrate Ingestion during Prolonged Cycling Improves Next-Day Time Trial Performance and Alters Amino Acid Concentrations.

Exercise with low carbohydrate availability increases protein degradation, which may reduce subsequent performance considerably. The present study aimed to investigate the effect of carbohydrate ingestion during standardized exercise with and without exhaustion on protein degradation and next-day performance. Seven trained male cyclists (V̇O 2max 66.8 ± 1.9 mL·kg -1 ·min -1 ; mean ± SEM) cycled to exhaustion (~2.5 h) at a power output eliciting 68% of V̇O 2max (W 68% ). This was followed by repeating 1-min work/1-min recovery intervals at 90% of V̇O 2max (W 90% ) until exhaustion. During W 68% , cyclists consumed a placebo water drink (PLA) the first time and a carbohydrate drink (CHO), 1 g carbohydrate·kg -1 ·h -1 , the second time. The participants performed the same amount of work under the two conditions, separated by at least 1 wk. A standardized diet was provided to the participants so that the two conditions were isoenergetic. To test the impact of carbohydrates on recovery, participants completed a time trial (TT) the next day. Carbohydrate ingestion maintained carbohydrate availability during W 68% and W 90% : total carbohydrate oxidation was significantly higher in CHO ( P = 0.022), and plasma glucose concentration was maintained compared with PLA ( P = 0.025). Next-day performance during TT was better after CHO ingestion (CHO, 41:49 ± 1:38 min; PLA, 42:50 ± 1:46 min; P = 0.020; effect size d = 0.23, small), as was gross efficiency (CHO, 18.6% ± 0.3%; PLA, 17.9% ± 0.3%; P = 0.019). Urinary nitrogen excretion ( P = 0.897) and urinary 3-methylhistidine excretion ( P = 0.673) did not significantly differ during the study period. Finally, tyrosine and phenylalanine plasma concentrations increased in PLA but not in CHO ( P = 0.018). Carbohydrate ingestion during exhaustive exercise reduced deterioration in next-day performance through reduced metabolic stress and development of fatigue. In addition, some parameters point toward less protein degradation, which would preserve muscle function.

GCPII Inhibition Delays Age-related Loss of Muscle Mass and Function in Mice

Sarcopenia, the age-related loss of skeletal muscle mass and function, is a significant problem that reduces the quality of life in the elderly. Despite the growing prevalence of sarcopenia, there is still a lack of effective therapies for this disease. Recent research has focused on the role of the enzyme glutamate carboxypeptidase II (GCPII) in regulating muscle function and neuromuscular junction (NMJ) integrity. We have previously shown that inhibition of GCPII with the potent inhibitor 2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) can significantly delay muscle function loss and NMJ denervation in an animal model of ALS. Given that sarcopenia shares similarities with ALS in terms of NMJ deterioration, we aimed to investigate whether 2-PMPA treatment could also preserve muscle function during aging. We measured the activity of GCPII in the gastrocnemius muscles of 4-month-old and 20-month-old mice, and found that GCPII activity was significantly increased in the 20-month-old mice (3188±182 fmol/mg/h) compared to 4-month-old mice (2009±317 fmol/mg/h). Then we treated 15-month-old C57BL6/J mice with 100mg/kg of 2-PMPA IP daily for 5 months and monitored muscle function. After 5 months of 2-PMPA treatment, we observed preservation of gastrocnemius muscle mass (164.8±5.6 vs. 143.6±6.4 mg, 2-PMPA vs. vehicle treated group) and a significant delay in age-related loss in grip strength (-4.75±3.22% vs. -20.98±3.73%, 2-PMPA vs. vehicle). We also found that 2-PMPA treatment increased the mean single-fiber cross-sectional area (759.4±5.2 vs. 722.4±5.1 μm 2 , 2-PMPA vs. vehicle), delayed the decline of nerve signals to the muscles as observed by compound muscle action potential (CMAP) amplitude decline (-7.37±6.16% vs. -26.05±3.71%, 2-PMPA vs. vehicle), and improved ambulation in old mice (3941±153 vs. 3216±188 beam brakes, 2-PMPA vs. vehicle) as observed by open-field test. Immunofluorescent staining showed that GCPII expression in aged muscle is associated with infiltrating macrophages, indicating inflammation as one potential target for the role of 2-PMPA in preserving muscle function during aging. Overall, our current results support that excessive GCPII activity is associated with muscle aging and GCPII inhibition is a potential therapeutic strategy for sarcopenia. This study highlights the potential of GCPII inhibition as a new therapeutic approach to preserving muscle function in the elderly. This work was supported by NIH R01 AG078181-01 (to BSS), R01 AG068130 (to BSS), R01NS093416 (to BSS), and R25GM109441 (Hopkins PREP support for TRJ). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be an option for DMD patients. We focused on amnion-derived mesenchymal stromal cells (AMSCs), a clinically viable cell source owing to their unique characteristics, such as non-invasive isolation, mitotic stability, ethical acceptability, and minimal risk of immune reaction and cancer. We aimed to identify novel immunomodulatory effects of AMSCs on macrophage polarization and their transplantation strategies for the functional recovery of skeletal and cardiac muscles.MethodsWe used flow cytometry to analyze the expression of anti-inflammatory M2 macrophage markers on peripheral blood mononuclear cells (PBMCs) co-cultured with human AMSCs (hAMSCs). hAMSCs were intravenously injected into DMD model mice (mdx mice) to assess the safety and efficacy of therapeutic interventions. hAMSC-treated and untreated mdx mice were monitored using blood tests, histological examinations, spontaneous wheel-running activities, grip strength, and echocardiography.ResultshAMSCs induced M2 macrophage polarization in PBMCs via prostaglandin E2 production. After repeated systemic hAMSC injections, mdx mice exhibited a transient downregulation of serum creatin kinase. Limited mononuclear cell infiltration and a decreased number of centrally nucleated fibers were indicative of regenerated myofibers following degeneration, suggesting an improved histological appearance of the skeletal muscle of hAMSC-treated mdx mice. Upregulated M2 macrophages and altered cytokine/chemokine expressions were observed in the muscles of hAMSC-treated mdx mice. During long-term experiments, a significant decrease in the grip strength in control mdx mice significantly improved in the hAMSC-treated mdx mice. hAMSC-treated mdx mice maintained running activity and enhanced daily running distance. Notably, the treated mice could run longer distances per minute, indicating high running endurance. Left ventricular function in DMD mice improved in hAMSC-treated mdx mice.ConclusionsEarly systemic hAMSC administration in mdx mice ameliorated progressive phenotypes, including pathological inflammation and motor dysfunction, resulting in the long-term improvement of skeletal and cardiac muscle function. The therapeutic effects might be associated with the immunosuppressive properties of hAMSCs via M2 macrophage polarization. This treatment strategy could provide therapeutic benefits to DMD patients.

Activation of eIF4E-binding-protein-1 rescues mTORC1-induced sarcopenia by expanding lysosomal degradation capacity.

Chronic mTORC1 activation in skeletal muscle is linked with age-associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E-binding proteins (4EBPs). Whole-body knockout of S6K1 or muscle-specific over-expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1-mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1-mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear. Mice with myofiber-specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1-mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt-TSC1mKO or S6K1-TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development. Here, we show that 4EBP1mt-TSC1mKO, but not S6K1-TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P<0.001) and strength (36.8% increase compared with TSC1mKO, P<0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two-fold reduction compared with TSC1mKO, P<0.05) and restored autophagy flux without relieving mTORC1-mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5-fold reduction compared with TSC1mKO, P<0.05) in muscle and restored mitochondrial homeostasis and function. We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.

Ubiquitin Ligases in Longevity and Aging Skeletal Muscle.

The development and prevalence of diseases associated with aging presents a global health burden on society. One hallmark of aging is the loss of proteostasis which is caused in part by alterations to the ubiquitin–proteasome system (UPS) and lysosome–autophagy system leading to impaired function and maintenance of mass in tissues such as skeletal muscle. In the instance of skeletal muscle, the impairment of function occurs early in the aging process and is dependent on proteostatic mechanisms. The UPS plays a pivotal role in degradation of misfolded and aggregated proteins. For the purpose of this review, we will discuss the role of the UPS system in the context of age-related loss of muscle mass and function. We highlight the significant role that E3 ubiquitin ligases play in the turnover of key components (e.g., mitochondria and neuromuscular junction) essential to skeletal muscle function and the influence of aging. In addition, we will briefly discuss the contribution of the UPS system to lifespan. By understanding the UPS system as part of the proteostasis network in age-related diseases and disorders such as sarcopenia, new discoveries can be made and new interventions can be developed which will preserve muscle function and maintain quality of life with advancing age.

MicroRNA cargo of extracellular vesicles released by skeletal muscle fibro-adipogenic progenitor cells is significantly altered with disuse atrophy and IL-1β deficiency.

Fibro-adipogenic progenitor cells (FAPs) are a population of stem cells in skeletal muscle that play multiple roles in muscle repair and regeneration through their complex secretome; however, it is not well understood how the FAP secretome is altered with muscle disuse atrophy. Previous work suggests that the inflammatory cytokine IL-1β is increased in FAPs with disuse and denervation. Inflammasome activation and IL-1β secretion are also known to stimulate the release of extracellular vesicles (EVs). Here, we examined the microRNA (miRNA) cargo of FAP-derived, platelet-derived growth factor receptor A (PDGFRα+) EVs from hindlimb muscles of wild-type and IL-1β KO mice after 14 days of single-hindlimb immobilization. Hindlimb muscles were isolated from mice following the immobilization period, and PDGFRα+ extracellular vesicles were isolated using size-exclusion chromatography and immunoprecipitation. Microarrays were performed to detect changes in miRNAs with unloading and IL-1β deficiency. Results indicate that the PDGFRα+, FAP-derived EVs show a significant increase in miRNAs, such as miR-let-7c, miR-let-7b, miR-181a, and miR-124. These miRNAs have previously been demonstrated to play important roles in cellular senescence and muscle atrophy. Furthermore, the expression of these same miRNAs was not significantly altered in FAP-derived EVs isolated from the immobilized IL-1β KO. These data suggest that disuse-related activation of IL-1β can mediate the miRNA cargo of FAP-derived EVs, contributing directly to the release of senescence- and atrophy-related miRNAs. Therapies targeting FAPs in settings associated with muscle disuse atrophy may therefore have the potential to preserve muscle function and enhance muscle recovery.

Molecular Fingerprint of BMD Patients Lacking a Portion in the Rod Domain of Dystrophin.

BMD is characterized by a marked heterogeneity of gene mutations resulting in many abnormal dystrophin proteins with different expression and residual functions. The smaller dystrophin molecules lacking a portion around exon 48 of the rod domain, named the D8 region, are related to milder phenotypes. The study aimed to determine which proteins might contribute to preserving muscle function in these patients. Patients were subdivided, based on the absence or presence of deletions in the D8 region, into two groups, BMD1 and BMD2. Muscle extracts were analyzed by 2-D DIGE, label-free LC-ESI-MS/MS, and Ingenuity pathway analysis (IPA). Increased levels of proteins typical of fast fibers and of proteins involved in the sarcomere reorganization characterize BMD2. IPA of proteomics datasets indicated in BMD2 prevalence of glycolysis and gluconeogenesis and a correct flux through the TCA cycle enabling them to maintain both metabolism and epithelial adherens junction. A 2-D DIGE analysis revealed an increase of acetylated proteoforms of moonlighting proteins aldolase, enolase, and glyceraldehyde-3-phosphate dehydrogenase that can target the nucleus promoting stem cell recruitment and muscle regeneration. In BMD2, immunoblotting indicated higher levels of myogenin and lower levels of PAX7 and SIRT1/2 associated with a set of proteins identified by proteomics as involved in muscle homeostasis maintenance.

Physiological Changes Associated with Space Missions: How Physical Exercise Helps

Physiological Changes Associated with Space Missions: How Physical Exercise Helps

Metabolic and Redox Biomarkers in Skeletal Muscle Underlie Physiological Adaptations of Two Estivating Anuran Species in a South American Semi-arid Environment.

The upregulation of endogenous antioxidants (i.e., preparation for oxidative stress, POS) is part of the biochemical responses underlying the adaptation of animals to adverse environments. Despite the phylogenetic diversity of animals in which POS has been described, most studies focus on animals under controlled laboratory conditions. To address this limitation, we have recently assessed the redox metabolism in the skeletal muscle of Proceratophrys cristiceps estivating under natural settings in the Caatinga. Here, we analyzed biochemical biomarkers in the muscle of another Caatinga species, Pleurodema diplolister, during the rainy (active) and dry (estivating frogs) seasons. We aimed to determine whether P. diplolister enhances its antioxidants during estivation under field conditions and to identify any effect of species on the biochemical responses of P. diplolister and P. cristiceps associated with estivation. To do so, we measured the activities of representative enzymes of intermediary metabolism and antioxidant systems, as well as glutathione and protein carbonyl levels, in the skeletal muscle of P. diplolister. Our findings revealed the suppression of oxidative metabolism and activation of antioxidant enzymes in estivating P. diplolister compared with active specimens. No changes in oxidative damage to proteins were observed and estivating P. diplolister had lower levels of disulfide glutathione (GSSG) and disulfide-to-total glutathione ratio (GSSG/tGSH) than those observed in active individuals. When data for P. diplolister and P. cristiceps were assembled and analyzed, significant effects of species were detected on the activities of metabolic enzymes (citrate synthase, isocitric dehydrogenase, malic enzyme, and creatine kinase) and antioxidant enzymes (catalase, glutathione peroxidase and glutathione transferase), as well as on GSSG/tGSH ratio. Such effects might underlie the physiological and behavioral differences between these two species that share the same microhabitat and survival strategy (i.e., to estivate) during the dry season. Despite some peculiarities, which reflect the physiological diversity of the mechanisms associated with estivation in the Brazilian Caatinga, both P. diplolister and P. cristiceps seem to balance the suppression of oxidative pathways, the maintenance of the capacity of oxygen-independent pathways, and the activation of endogenous antioxidants to preserve muscle function and be ready to resume activity whenever the unpredictable rainy period arrives.

Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.

Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders, and, of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling because these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors,” increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis, and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy, and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.

Dietary Protein Requirement Threshold and Micronutrients Profile in Healthy Older Women Based on Relative Skeletal Muscle Mass.

Although multiple nutrients have shown protective effects with regard to preserving muscle function, the recommended amount of dietary protein and other nutrients profile on older adults for maintenance of high muscle mass is still debatable. The aims of this paper were to: (1) identify dietary differences between older women with low and high relative skeletal muscle mass, and (2) identify the minimal dietary protein intake associated with high relative skeletal muscle mass and test the threshold ability to determine an association with skeletal muscle phenotypes. Older women (n = 281; 70 ± 7 years, 65 ± 14 kg), with both low and high relative skeletal muscle mass groups, completed a food questionnaire. Skeletal muscle mass, fat-free mass (FFM), biceps brachii thickness, vastus lateralis anatomical cross-sectional area (VLACSA), handgrip strength (HGS), maximum elbow flexion torque (MVCEF), maximum knee extension torque (MVCKE), muscle quality (HGS/Body mass), and fat mass were measured. Older women with low relative skeletal muscle mass had a lower daily intake of protein, iodine, polyunsaturated fatty acid (PUFA), Vit E, manganese, milk, fish, nuts and seeds (p < 0.05) compared to women with high relative skeletal muscle mass. The minimum required dietary protein intake for high relative skeletal muscle mass was 1.17 g/kg body mass/day (g/kg/d) (sensitivity: 0.68; specificity: 0.62). Women consuming ≥1.17 g/kg/d had a lower BMI (B = −3.9, p < 0.001) and fat mass (B = −7.8, p < 0.001), and a higher muscle quality (B = 0.06, p < 0.001). The data indicate that to maintain muscle mass and function, older women should consume ≥1.17 g/kg/d dietary protein, through a varied diet including milk, fish and nuts that also contain polyunsaturated fatty acid (PUFA) and micronutrients such as iodine, Vit E and manganese.

Exercise, but Not Metformin Prevents Loss of Muscle Function Due to Doxorubicin in Mice Using an In Situ Method.

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius–plantaris–soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content (p = 0.07) and AMPK phosphorylation (p < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.

The Role of Autophagy Modulated by Exercise in Cancer Cachexia.

Cancer cachexia is a syndrome experienced by many patients with cancer. Exercise can act as an autophagy modulator, and thus holds the potential to be used to treat cancer cachexia. Autophagy imbalance plays an important role in cancer cachexia, and is correlated to skeletal and cardiac muscle atrophy and energy-wasting in the liver. The molecular mechanism of autophagy modulation in different types of exercise has not yet been clearly defined. This review aims to elaborate on the role of exercise in modulating autophagy in cancer cachexia. We evaluated nine studies in the literature and found a potential correlation between the type of exercise and autophagy modulation. Combined exercise or aerobic exercise alone seems more beneficial than resistance exercise alone in cancer cachexia. Looking ahead, determining the physiological role of autophagy modulated by exercise will support the development of a new medical approach for treating cancer cachexia. In addition, the harmonization of the exercise type, intensity, and duration might play a key role in optimizing the autophagy levels to preserve muscle function and regulate energy utilization in the liver.

Murine models of Duchenne muscular dystrophy: is there a best model?

Murine models of Duchenne muscular dystrophy: is there a best model?