Skeletal muscle hypertrophy and attenuation of cardio-metabolic risk factors (SHARC) using functional electrical stimulation-lower extremity cycling in persons with spinal cord injury: study protocol for a randomized clinical trial.

BACKGROUND: Persons with spinal cord injury (SCI) are at heightened risks of developing unfavorable cardiometabolic consequences due to physical inactivity. Functional electrical stimulation (FES) and surface neuromuscular electrical stimulation (NMES)-resistance training (RT) have emerged as effective rehabilitation methods that can exercise muscles below the level of injury and attenuate cardio-metabolic risk factors. Our aims are to determine the impact of 12 weeks of NMES + 12 weeks of FES-lower extremity cycling (LEC) compared to 12 weeks of passive movement + 12 weeks of FES-LEC on: (1) oxygen uptake (VO2), insulin sensitivity, and glucose disposal in adults with SCI; (2) skeletal muscle size, intramuscular fat (IMF), and visceral adipose tissue (VAT); and (3) protein expression of energy metabolism, protein molecules involved in insulin signaling, muscle hypertrophy, and oxygen uptake and electron transport chain (ETC) activities. METHODS/DESIGN: Forty-eight persons aged 18-65 years with chronic (> 1 year) SCI/D (AIS A-C) at the C5-L2 levels, equally sub-grouped by cervical or sub-cervical injury levels and time since injury, will be randomized into either the NMES + FES group or Passive + FES (control group). The NMES + FES group will undergo 12 weeks of evoked RT using twice-weekly NMES and ankle weights followed by twice-weekly progressive FES-LEC for an additional 12 weeks. The control group will undergo 12 weeks of passive movement followed by 12 weeks of progressive FES-LEC. Measurements will be performed at baseline (B; week 0), post-intervention 1 (P1; week 13), and post-intervention 2 (P2; week 25), and will include: VO2 measurements, insulin sensitivity, and glucose effectiveness using intravenous glucose tolerance test; magnetic resonance imaging to measure muscle, IMF, and VAT areas; muscle biopsy to measure protein expression and intracellular signaling; and mitochondrial ETC function. DISCUSSION: Training through NMES + RT may evoke muscle hypertrophy and positively impact oxygen uptake, insulin sensitivity, and glucose effectiveness. This may result in beneficial outcomes on metabolic activity, body composition profile, mitochondrial ETC, and intracellular signaling related to insulin action and muscle hypertrophy. In the future, NMES-RT may be added to FES-LEC to improve the workloads achieved in the rehabilitation of persons with SCI and further decrease muscle wasting and cardio-metabolic risks. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02660073 . Registered on 21 Jan 2016.

Juzentaihoto Suppresses Muscle Atrophy in Streptozotocin-Induced Diabetic Mice.

In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy.

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

Electrically stimulated acupuncture increases renal blood flow through exosome-carried miR-181.

Acupuncture with low-frequency electrical stimulation (Acu/LFES) can prevent muscle atrophy by increasing muscle protein anabolism in mouse models of chronic kidney disease. During the treatment of muscle wasting, we found that Acu/LFES on the gastrocnemius muscle of the leg enhances renal blood flow. We also found that Acu/LFES increases exosome abundance and alters exosome-associated microRNA expression in the circulation. When exosome secretion was blocked using GW4869, the Acu/LFES-induced increase in renal blood flow was limited. This provided evidence that the increased renal blood flow is exosome mediated. To identify how exosomes regulate renal blood flow, we performed microRNA deep sequencing in exosomes isolated from treated and untreated mouse serum and found that the 34 microRNAs are altered by Acu/LFES. In particular, miR-181d-5p is increased in the serum exosome of Acu/LFES-treated mice. In silico searching suggested that miR-181d-5p could target angiotensinogen. Using a luciferase reporter assay, we demonstrated that miR-181 directly inhibits angiotensinogen. When Acu/LFES-treated muscle was excised and incubated in culture medium, we found that the amount of exosomes and miR-181d-5p was increased in the medium providing evidence that Acu/LFES can increase miR-181 secretion. We conclude that Acu/LFES on leg hindlimb increases miR-181 in serum exosome leading to increased renal blood flow. This study provides important new insights about the mechanism(s) by which acupuncture may regulation of muscle-organ cross talk through exosome-derived microRNA.

Melanocortin-4 receptor agonist (RO27-3225) ameliorates soleus but not gastrocnemius atrophy in arthritic rats.

Adjuvant-induced arthritis in rats decreases body weight and muscle mass. Melanocyte stimulating hormone administration to arthritic rats decreases inflammation and skeletal muscle wasting. In this study, we investigate whether activation of melanocortin-4 receptor by RO27-3225 administration is able to prevent the effect of arthritis on the expression of muscle-specific E3 ubiquitin ligases and MyoD in two different muscles, gastrocnemius (a mainly fast type muscle) and soleus (slow type). Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant. Control and arthritic rats were injected with RO27-3225 (180 µg/kg i.p. twice a day) or saline, for 8 days. Body weight change, food intake and arthritis index were assessed daily. After sacrifice, serum insulin-like growth factor -1 (IGF-1) and corticosterone, as well as nuclear factor-κB(p65), cyclooxygenase-2 (COX-2), atrogene and MyoD in gastrocnemius and soleus were analysed. Administration of RO27-3225 to arthritic rats decreased arthritis scores, hind paw volume as well as nuclear factor-κB(p65) phosphorylation in gastrocnemius and soleus. However, RO27-3225 was not able to modify the effects of arthritis on serum IGF-1 and corticosterone. RO27-3225 ameliorates arthritis-induced decrease in food intake, body weight gain, epidydimal white adipose tissue and soleus weight, but not in gastrocnemius weight. Arthritis increased COX-2, atrogin-1 and MuRF1 expression in gastrocnemius and soleus, whereas RO27-3225 prevented this increase in soleus but not in gastrocnemius. Arthritis also increased MyoD expression in gastrocnemius and soleus (P < 0.01). RO27-3225 decreased MyoD expression in gastrocnemius but not in soleus of arthritic rats. In control rats RO27-3225 did not modify MyoD expression in gastrocnemius or soleus. In conclusion, our data suggest that in arthritic rats, RO27-3225 treatment decreases inflammation and muscle atrophy, preventing atrogene upregulation in slow type muscle but not in gastrocnemius. The lack of effect in the gastrocnemius can be related to the inability of RO27-3225 to prevent arthritis-induced corticosterone upregulation as well as IGF-1 downregulation.

Anabolic resistance assessed by oral stable isotope ingestion following bed rest in young and older adult volunteers: Relationships with changes in muscle mass.

BACKGROUND & AIMS: Aging and experimental bed rest are associated with muscle atrophy and resistance to post-prandial stimulation of protein synthesis or anabolic resistance (AR). We have used in young and older adult volunteers, during short-term bed rest, a quick and non-invasive method, based on a single oral bolus of the stable isotope L[ring-2H5]phenylalanine (D5Phe), to determine post-prandial AR, defined as ratio between irreversible hydroxylation and incorporation into body protein of ingested phenylalanine. METHODS: We compared in older (O, 59 ± 1 y) and young (Y, 23 ± 1 y) healthy male volunteers the effects of two-week bed rest on post-prandial protein kinetics, assessed during absorption of a standard ready-to-use oral nutritional supplement, through stable-labeled isotope amino acid D5Phe, diluted in water, given as single oral load. The metabolic fate of D5Phe is either utilization for protein synthesis or irreversible hydroxylation to L[ring-2H4]tyrosine (D4Tyr). AR was defined as ratio between the areas under the curves of D4Tyr-to-D5Phe plasma concentrations over 6 h meal absorption. To determine the relationships between AR and muscle changes following bed rest, quadriceps muscle volume (QMV) was determined by magnetic resonance imaging (MRI). RESULTS: At baseline, in pooled Y and O subjects, values of AR were inversely correlated with QMV (R = -0.75; p < 0.03). Following 2-weeks of inactivity, there were significant bed rest effects on AR (p < 0.01) and QMV (p < 0.03), as well as significant bed rest × group interaction for AR (p < 0.03; +9.2% in Y; +21.9% in O) and QMV (p < 0.05; -5.7% in Y; -%7.3 in O). In pooled subjects, the percentage delta changes in AR and QMV, induced by bed rest, were inversely correlated (R = -0.57; p < 0.05). CONCLUSION: Bed rest-induced AR is much greater in the older than in younger adults. We have developed a new, simple, non-invasive method for the assessment of AR. The results indicate that this metabolic abnormality is a key mechanism for sarcopenia of aging and inactivity.

Hypothalamic activation is essential for endotoxemia-induced acute muscle wasting.

Growing evidence suggests acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in critical patients. Previously, plenty of studies of muscle wasting focused on the peripheral pathway, little was known about the central role. We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process. In lipopolysaccharide (LPS) treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of nuclear factor kappa-B (NF-κB) pathway activation by infusion of an inhibitor (PS1145) can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide proopiomelanocortin (POMC) expression with a lentiviral vector containing shRNA can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected. Taken together, these results suggest activation of hypothalamic POMC is pivotal for acute muscle wasting caused by endotoxemia. Neuropeptide POMC expression may have mediated the contribution of hypothalamic inflammation to peripheral muscle wasting. Pharmaceuticals with the ability of inhibiting hypothalamic NF-κB pathway or POMC activation may have a therapeutic potential for acute muscle wasting and nutritional therapy in septic patients.

Electroestimulación neuromuscular intradiálisis, fuerza muscular, capacidad funcional y composición corporal / Intradialysis neuromuscular electro stimulation muscle strength, functional capacity and body composition

Introducción: La capacidad funcional disminuida y la importante atrofia muscular caracterizan a los pacientes en hemodiálisis (HD). El ejercicio físico intradiálisis y recientemente la electroestimulación neuromuscular (EMS), representan dos serias opciones terapéuticas para mejorar esta deteriorada condición física. Actualmente, no existen estudios publicados sobre el papel de la EMS y la composición corporal en los pacientes en HD. Objetivo: Analizar que efecto produce un programa de EMS sobre la fuerza muscular, capacidad funcional, parámetros nutricionales y composición corporal en nuestros pacientes en HD. Material y Métodos: Estudio unicéntrico, prospectivo de 12 semanas de duración. Los pacientes incluidos realizaron un programa adaptativo de EMS en ambos cuádriceps intradiálisis mediante el dispositivo Compex R Theta 500i. Analizamos: 1.- Parámetros nutricionales (Albumina, pre albúmina, triglicéridos, colesterol total y fracciones, ferritina y Proteína C reactiva). 2.- Datos musculares: Composición muscular cuadriceps, Fuerza extensión máxima cuádriceps (FEMQ) y handgrip (HG) brazo dominante. 3.- Test funcionales: “Sit to stand to sit” (STS10) y “six- minutes walking test” (6MWT). 4.- Composición corporal mediante biompedancia electrica (BIA). Resultados: 13 pacientes incluidos: (69.2% hombres). Edad media: 65.7 años y 33.9 meses en HD. I.Charlson medio 9.1. La principal etiología de la ERC fue la DM ( 38.5%). Al final del estudio se observó una mejoría en (*p<0.05): FEMQ* ( 11.7±7.1 vs 13.4±7.4 Kg), STS10 (39.3±15.5 vs 35.8±13.7 seg), 6MWT* (9.9%, 293.2 vs 325.2 m). En relación a la composición corporal, se observó únicamente un aumento significativo del área muscular (AMQ*: 128.6 ± 30.2 vs 144.6 ± 22.4 cm2) y una disminución del área grasa (AGQ*: 76.5 ± 26.9 vs 62.1 ± 20.1 cm2) a nivel quadricipital, sin cambios en el resto de datos analizados (% grasa abdominal, peso graso, peso magro, agua corporal total). No se objetivaron cambios relevantes en los parámetros nutricionales y de adecuación dialítica. Conclusiones: 1.- La electroestimulación neuromuscular intradialísis mejoró la fuerza muscular, la capacidad funcional y la composición muscular del cuadriceps de nuestros pacientes en HD. 2.- Nuestros resultados remarcan el carácter local de la electroes-timulación neuromuscular, dada la ausencia de cambios relevantes en el resto de los parámetros nutricionales y datos corporales analizados. 3.- No obstante, son necesarios futuros estudios mejor diseñados, de cara a discernir si la electroestimulación neuromuscular podría ser una nueva alternativa terapéutica para evitar la atrofia muscular y el deterioro progresivo de la condición física de éstos pacientes (AU)

Background: The reduced functional capacity and significant muscle atrophy characterized patients on hemodialysis. Intradialytic exercise and recently neuromuscular electrostimulation (EMS) represent two serious therapeutical options to improve the deteriorated physical condition. Until date, there are no published studies about the role of EMS and body composition in HD patients. Objectives: Analyze the effect a program of EMS on muscle strength, functional capacity, nutritional parameters and body composition in our HD patients. Methods: A 12 weeks single-center, prospective study. Patients included in the study performed an intradialysis EMS adaptive program in both quadriceps using the Compex R Theta 500i device. We analyzed: 1.- Nutritional parameters (albumin, pre-albumin, triglycerides, total cholesterol and fractions, ferritin and C-reactive protein). 2.- Muscular data: Muscular composition, Maximum length quadriceps strength (MLQS) and “hand-grip” (HG) dominant arm. 3.- Functional capacity test: “Sit to stand to sit” (STS10) and “six- minutes walking test” (6MWT). 4.- Body composition. Results: 13 HD patients included: 69.2 % men. Mean age 65.7 years and 33.9 months on HD. A significant (* p < 0,05) improvement was observed in MLQS* (11.7±7.1 vs 13.4±7.4 Kg), STS10* (39.3±15.5 vs 35.8±13.7 seg), 6MWT* (9.9%, 293.2 vs 325.2 m). There was a signi-ficant increase in the quadriceps muscular area (QMA*: 128.6 ± 30.2 vs 144.6 ± 22.4 cm2) and decrease of fat quadricipital area (FQA*: 76.5 ± 26.9 vs 62.1 ± 20.1 cm2). No significant changes were observed in nutritional parameters, body composition (body fat percentage, lean and fat mass, total body water) or dialysis adecuacy data. Conclusions: 1.- Intradialysis quadriceps EMS improved muscle strength, functional capacity and the quadriceps muscle composition in our HD patients. 2.- Our results underline the local aspects on EMS, given the absence of relevant changes on nutritional parameters and body composition. 3.- Future studies are manadatory in order to establish if EMS could be a new alternative to prevent muscle atrophy and the progressive deterioration of the physical condition of these patients (AU)

Apple Pomace Extract Improves Endurance in Exercise Performance by Increasing Strength and Weight of Skeletal Muscle.

Ursolic acid is a lipophilic pentacyclic triterpenoid found in many fruits and herbs and is used in several herbal folk medicines for diabetes. In this study, we evaluated the effects of apple pomace extract (APE; ursolic acid content, 183 mg/g) on skeletal muscle atrophy. To examine APE therapeutic potential in muscle atrophy, we investigated APE effects on the expression of biomarkers associated with muscle atrophy and hypertrophy. We found that APE inhibited atrophy, while inducing hypertrophy in C2C12 myotubes by decreasing the expression of atrophy-related genes and increasing the expression of hypertrophy-associated genes. The in vivo experiments using mice fed a diet with or without APE showed that APE intake increased skeletal muscle mass, as well as grip strength and exercise capacity. In addition, APE significantly improved endurance in the mice, as evidenced by increased exhaustive running time and muscle weight, and reduced the expression of the genes involved in the development of muscle atrophy. APE also decreased the concentration of serum lactate and lactate dehydrogenase, inorganic phosphate, and creatinine, the indicators of accumulated fatigue and exercise-induced stress. These results suggest that APE may be useful as an ergogenic functional food or dietary supplement.

Early exercise after spinal cord injury ('Switch-On'): study protocol for a randomised controlled trial.

BACKGROUND: Spinal cord injury (SCI) leads to a profound muscular atrophy, bone loss and bone fragility. While there is evidence that exercising paralysed muscles may lead to reversal of muscle atrophy in the chronic period after SCI, there is little evidence that exercise can prevent muscle changes early after injury. Moreover, whether exercise can prevent bone loss and microarchitectural decay is not clear. METHODS/DESIGN: A multi-centre, parallel group, assessor-blinded randomised controlled trial will be conducted. Fifty participants with acute spinal cord injury will be recruited from four SCI units in Australia and New Zealand. Participants will be stratified by site and AIS status and randomised to an experimental or control group. Experimental participants will receive a 12-week programme of functional electrical stimulation (FES)-assisted cycling. Control participants will receive a 12-week programme of passive cycling. The primary outcome is muscle cross-sectional area of the thigh and calf measured using magnetic resonance images (MRI) of the leg. Secondary outcomes include serum biomarkers of SCI osteoporosis (sclerostin, P1NP and ß-CTX), markers of immune function (IL-6, IL-10, FGF2, INF-γ, TNF-α), neurological function, body composition, depression and quality of life. Leg MRIs will be measured by a single blinded assessor based in Melbourne. Serum samples will be analysed in a central laboratory. All other characteristics will be measured at baseline and 12 weeks by blinded and trained assessors at each site. The first participant was randomised on 27 November 2012. DISCUSSION: The results of this trial will determine the relative effectiveness of a 12-week programme of FES-assisted cycling versus passive cycling in preventing muscle atrophy and maintaining skeletal integrity after spinal cord injury. TRIAL REGISTRATION: ACTRN12611001079932 (18 October 2011).

Vitamin D and muscle function in the elderly: the elixir of youth?

PURPOSE OF REVIEW: Circumstantial evidence suggests that vitamin D deficiency may contribute to age-related changes in skeletal muscle. This review discusses recent clinical trials examining effects of vitamin D on muscle function in the elderly, and poses the important question: can vitamin D reverse muscle ageing? RECENT FINDINGS: Observational studies report an association between vitamin D and muscle atrophy/weakness in elderly subjects. Interventional studies suggest that frail, elderly subjects may benefit from vitamin D supplementation by displaying reduced falls, improved muscle function and increased muscle fibre size. However, meta-analyses do not report convincing effects of vitamin D in the elderly. This may be because of multiple factors including lack of standardized endpoints for muscle function, variable study design and different doses of vitamin D supplementation amongst these studies. The evidence base is therefore inconsistent. SUMMARY: Vitamin D deficiency may exacerbate ageing of skeletal muscle. However, current evidence that vitamin D supplementation reverses age-related muscle dysfunction is equivocal and does not justify stringent vitamin D targets in the elderly. Until these issues are clarified, the safest option is to aim for conservative vitamin D targets that are sufficient for normal calcium homeostasis.

Dosing schedule-dependent attenuation of dexamethasone-induced muscle atrophy in mice.

Many inflammatory and autoimmune diseases are treated using synthetic glucocorticoids. However, excessive glucocorticoid can often cause unpredictable effects including muscle atrophy. Endogenous glucocorticoid levels robustly fluctuate in a circadian manner and peak just before the onset of the active phase in both humans and nocturnal rodents. The present study determines whether muscle atrophy induced by exogenous glucocorticoid can be avoided by optimizing dosing times. We administered single daily doses of the glucocorticoid analog dexamethasone (Dex) to mice for 10 days at the times of day corresponding to peak (early night) or trough (early morning) endogenous glucocorticoid levels. Administration at the acrophase of endogenous glucocorticoids significantly attenuated Dex-induced wasting of the gastrocnemius (Ga) and tibialis anterior (TA) muscles that comprise mostly fast-twitch muscle fibers. Real-time RT-PCR revealed that the Dex-induced mRNA expression of genes encoding the atrophy-related ubiquitin ligases Muscle Atrophy F-box (Fbxo32, also known as MAFbx/Atrogin-1) and Muscle RING finger 1 (Trim63, also known as MuRF1) in the Ga and TA muscles was significantly attenuated by Dex when administered during the early night. Dex negligibly affected the weight of the soleus (So) muscle that mostly comprises slow-twitch muscle fibers, but significantly and similarly decreased the weight of the spleen at both dosing times. These results suggest that glucocorticoid-induced muscle atrophy can be attenuated by optimizing the dosing schedule.

Serum 25-hydroxyvitamin D and muscle atrophy in the elderly.

The objective of this review is to consider the mechanisms by which vitamin D affects muscle and the evidence that vitamin D status is important for muscle performance and fall prevention in older adults. Vitamin D receptors have been identified in human skeletal-muscle cells. Activation of these receptors by 1,25-dihydroxyvitamin D is involved in the action of vitamin D on the myocyte. Several studies have examined the effect of supplemental vitamin D on muscle strength, balance and falls. Among those examining muscle strength, results have been either positive for vitamin D or null. A recent meta-analysis of seventeen such trials revealed no significant effect of vitamin D overall, but a significant improvement in strength was observed in the trials in which the mean starting level of 25-hydroxyvitamin D was 25 nmol/l or below. Evidence for an effect of vitamin D on balance, measured as sway, is less abundant but more consistently positive. Many trials have evaluated the effect of supplemental vitamin D on falls. Overall, there is about a 20% lower risk of falling with supplementation. One meta-analysis considered the vitamin D dose administered and concluded that doses up through 15 µg (600 IU) were ineffective and doses of 17·5-25 µg/d (700-1000 IU/d) significantly lowered fall risk. The minimal 25-hydroxyvitamin D level needed for benefit was 60 nmol/l.

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle.

Supra-physiological levels of vitamin D induce skeletal muscle atrophy, which may be particularly detrimental in already sarcopaenic elderly. Neither the cause nor whether the atrophy is fibre type specific are known. To obtain supraphysiological levels of circulating vitamin D (1,25(OH)(2)D(3)) 27.5-month-old female Fischer(344) × Brown Norway F1 rats were orally treated for 6 weeks with vehicle or the vitamin D analogue alfacalcidol. Alfacalcidol treatment induced a 22% decrease in body mass and 17% muscle atrophy. Fibre atrophy was restricted to type IIb fibres in the low-oxidative part of the gastrocnemius medialis only (-22%; P < 0.05). There was a concomitant 1.6-fold increase in mRNA expression of the ubiquitin ligase MuRF-1 (P < 0.001), whereas those of insulin-like growth factor 1 and myostatin were not affected. Circulating IL-6 was unaltered, but leptin and adiponectin were decreased (-39%) and increased (64%), respectively. The treated rats also exhibited a reduced food intake. In conclusion, supraphysiological levels of circulating 1,25(OH)(2)D(3) cause preferential atrophy of type IIb fibres, which is associated with an increased expression of MuRF-1 without evidence of systemic inflammation. The atrophy and loss of body mass in the presence of supra-physiological levels of vitamin D are primarily due to a reduced food intake.

[Effect of Ligusticum and its two main components on muscle atrophy in a hind limb unloaded rat model].

OBJECTIVE: To study the effects of Ligusticum and its two components (Sodium Ferulate and Ligustrazine as main efficacy components in Ligusticum for invigorating blood circulation) on muscle atrophy in a hind limb unloaded rat model. METHODS: The tail-suspended rats were subjected to a 14-days disuse, immunohistochemistry and hemorheology were used to study the effects of medicines on soleus muscle. RESULTS: Compared with HLU+ W: (1) The CSA of soleus type I fibers in HLU + SfH and HLU+ TmpH increased by 37.3% and 39.4% respectively (P < 0.05). (2) Expression level of MHC II were inhibited in all treatment groups (P < 0.01). (3) Expression of MHC II in nuclear bag 2 fiber were altered from positive to negative. (4) The blood viscosity in low shear rates decreased obviously (P < 0.01), even near to control. CONCLUSION: Ligusticum and its two main efficacy components (Sodium Ferulate and Ligustrazine) can prevent soleus atrophy induced by disuse, and Sodium Ferulate and Ligustrazine in high dose showed most efficacy.

Leucine attenuates skeletal muscle wasting via inhibition of ubiquitin ligases.

The aim of this study was to assess the effect of leucine supplementation on elements of the ubiquitin-proteasome system (UPS) in rat skeletal muscle during immobilization. This effect was evaluated by submitting the animals to a leucine supplementation protocol during hindlimb immobilization, after which different parameters were determined, including: muscle mass; cross-sectional area (CSA); gene expression of E3 ligases/deubiquitinating enzymes; content of ubiquitinated proteins; and rate of protein synthesis. Our results show that leucine supplementation attenuates soleus muscle mass loss driven by immobilization. In addition, the marked decrease in the CSA in soleus muscle type I fibers, but not type II fibers, induced by immobilization was minimized by leucine feeding. Interestingly, leucine supplementation severely minimized the early transient increase in E3 ligase [muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1] gene expression observed during immobilization. The reduced peak of E3 ligase gene expression was paralleled by a decreased content of ubiquitinated proteins during leucine feeding. The protein synthesis rate decreased by immobilization and was not affected by leucine supplementation. Our results strongly suggest that leucine supplementation attenuates muscle wasting induced by immobilization via minimizing gene expression of E3 ligases, which consequently could downregulate UPS-driven protein degradation. It is notable that leucine supplementation does not restore decreased protein synthesis driven by immobilization.

Vitamin E and C supplementation does not ameliorate muscle dysfunction after anterior cruciate ligament surgery.

Muscle atrophy and weakness are predominant impairments after anterior cruciate ligament (ACL) surgical repair. We tested the hypothesis that vitamin E and C supplementation will improve recovery from ACL injury. Men undergoing elective ACL surgery were randomly assigned to twice-daily supplements of either antioxidants (AO; vitamins E and C, n=10) or matching placebos (n=10) from 2 weeks before until 3 months after surgery. Each subject provided several fasting blood draws, two muscle biopsies from the thigh muscle of the injured limb, and strength and thigh circumference measurements of the lower limbs. Muscle atrophy was apparent in both groups before and several days after surgery. Compared with baseline measurements, peak isometric force of the injured limb increased significantly (P<0.05) by 3 months postsurgery in both treatment groups; however, AO supplementation did not augment these strength gains. By contrast, baseline plasma ascorbic acid concentrations correlated (r=0.59, P=0.006) with subsequent improvement in the strength of the injured limb. In summary, vitamin E and C supplementation was ineffective in potentiating the improvement in force production by the injured limb; however, baseline vitamin C status was associated with beneficial outcomes in strength, suggesting that long-term dietary habits are more effective than short-term supplements.

The dose-dependent effects of testosterone on sexual function and on muscle mass and function.

Testosterone dose-response relationships are central to the issue of testosterone replacement therapy, within the context of both hypogonadal men and older men with declining testosterone levels. Dosages are also important when considering anabolic applications of testosterone for treating sarcopenia associated with chronic illness. The critical issue is whether increases in muscle mass and function can be achieved with dosages that will not adversely affect lipid profile, cardiovascular risk, and the prostate. The dose-response relationship and mechanisms of androgen action on the muscle for controlling it are being investigated.

Low serum calcidiol concentration in older adults with reduced muscular function.

OBJECTIVE: To examine the association between muscular function and the serum concentrations of 25-hydroxyvitamin D (calcidiol) and 1,25-dihydroxyvitamin D (calcitriol). DESIGN: A randomized population survey. Baseline measurements of serum calcidiol and calcitriol concentrations and assessment of muscular function (hand grip strength, ability to climb stairs, outdoor activity, and fall occurrence). SETTING: The Medical department, Aker University Hospital, Oslo, and subjects' homes. PARTICIPANTS: Two hundred forty-six recently hospitalized older patients and 103 randomly selected older people living at home. MEASUREMENTS: Serum concentration of calcidiol and calcitriol in relation to muscle function. MAIN RESULTS: Reduced muscle function was associated with low calcidiol levels. In both the hospital group and the home group, calcidiol concentrations correlated positively to arm muscle strength (r = .22, P < .001; r = .37, P < .001), ability to climb stairs (r = -.16, P < .05; r = -.42, P = < .001), physical activity (r = -.27, P < .001; r = -.31, P < .001), and the absence of fall occurrences (r = -.27, P < .001; r = -.31, P = .004). Calcitriol showed an association with physical activity in the hospital group (r = -.19, P < .05), and with fall last month in the home group (r = -.22, P < .05). CONCLUSIONS: Older people with reduced muscle function often had reduced levels of calcidiol serum concentration. Low levels of calcidiol were not associated with signs of general undernutrition, such as low body mass, or with reduced arm-muscle circumference or triceps skinfold thickness. This finding may suggest a physiological role for calcidiol in muscle function. Reduced muscle strength increased disability in our older subjects, which may be improved by vitamin D supplementation in vitamin D-deficient subjects.

Carnitine and weakness in haemodialysis patients.

Weakness in haemodialysis patients has been attributed to several factors including carnitine deficiency. Malnutrition, neuropathy, uraemic myopathy and parathyroid hormone excess may all be important. Six haemodialysis patients were shown to have reduced muscle power compared with a normal population, and to be malnourished by dietary assessment, and features of their weakness were investigated. Total carnitine was normal in plasma but elevated in muscle, with an excess of esterified carnitine in both plasma and muscle and diminished free plasma carnitine. Muscle biopsy showed no features of carnitine deficiency and electromyography showed a non-specific neuropathy with additional myopathic changes in some. Dietary supplementation with L-carnitine (2 g/day) for 6 weeks in a placebo-controlled trial showed a redistribution of carnitine fractions but no subjective or objective improvement in muscle function. There was no improvement in the plasma lipid profile. The weakness of haemodialysis patients is multifactorial. We have not demonstrated total carnitine depletion in either muscle or plasma, and oral supplementation of L-carnitine has no demonstrable effect in this group.