Showing papers on "Skeletal muscle published in 2007"
TL;DR: The data indicate that AMPK phosphorylation of PGC-1α initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
Abstract: Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1α gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1α, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1α itself are almost entirely dependent on the function of PGC-1α protein. Furthermore, AMPK phosphorylates PGC-1α directly both in vitro and in cells. These direct phosphorylations of the PGC-1α protein at threonine-177 and serine-538 are required for the PGC-1α-dependent induction of the PGC-1α promoter. These data indicate that AMPK phosphorylation of PGC-1α initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
2,038 citations
TL;DR: FoxO3 controls the two major systems of protein breakdown in skeletal muscle, the ubiquitin-proteasomal and autophagic/lysosomal pathways, independently and is pointed to as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved.
1,747 citations
TL;DR: In conclusion, injured skeletal muscle recruits monocyte (MO) exhibiting inflammatory profiles that operate phagocytosis and rapidly convert to antiinflammatory MPs that stimulate myogenesis and fiber growth.
Abstract: Macrophages (MPs) are important for skeletal muscle regeneration in vivo and may exert beneficial effects on myogenic cell growth through mitogenic and antiapoptotic activities in vitro. However, MPs are highly versatile and may exert various, and even opposite, functions depending on their activation state. We studied monocyte (MO)/MP phenotypes and functions during skeletal muscle repair. Selective labeling of circulating MOs by latex beads in CX3CR1GFP/+ mice showed that injured muscle recruited only CX3CR1lo/Ly-6C+ MOs from blood that exhibited a nondividing, F4/80lo, proinflammatory profile. Then, within muscle, these cells switched their phenotype to become proliferating antiinflammatory CX3CR1hi/Ly-6C− cells that further differentiated into F4/80hi MPs. In vitro, phagocytosis of muscle cell debris induced a switch of proinflammatory MPs toward an antiinflammatory phenotype releasing transforming growth factor β1. In co-cultures, inflammatory MPs stimulated myogenic cell proliferation, whereas antiinflammatory MPs exhibited differentiating activity, assessed by both myogenin expression and fusion into myotubes. Finally, depletion of circulating MOs in CD11b–diphtheria toxin receptor mice at the time of injury totally prevented muscle regeneration, whereas depletion of intramuscular F4/80hi MPs at later stages reduced the diameter of regenerating fibers. In conclusion, injured skeletal muscle recruits MOs exhibiting inflammatory profiles that operate phagocytosis and rapidly convert to antiinflammatory MPs that stimulate myogenesis and fiber growth.
1,664 citations
TL;DR: It is concluded that satellite cells are a heterogeneous population composed of stem cells and committed progenitors, and this work provides critical insights into satellite cell biology and open new avenues for therapeutic treatment of neuromuscular diseases.
1,254 citations
TL;DR: This review focuses on recent advances on the biology of GLUT4, the principal glucose transporter protein that mediates glucose uptake into skeletal muscle and plays a key role in regulating whole body glucose homeostasis.
1,184 citations
TL;DR: Data show that myogenic precursors, distinct from satellite cells, are associated with microvascular walls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' present after birth and may be a promising candidate for future cell-therapy protocols in patients.
Abstract: Cells derived from blood vessels of human skeletal muscle can regenerate skeletal muscle, similarly to embryonic mesoangioblasts. However, adult cells do not express endothelial markers, but instead express markers of pericytes, such as NG2 proteoglycan and alkaline phosphatase (ALP), and can be prospectively isolated from freshly dissociated ALP(+) cells. Unlike canonical myogenic precursors (satellite cells), pericyte-derived cells express myogenic markers only in differentiated myotubes, which they form spontaneously with high efficiency. When transplanted into severe combined immune deficient-X-linked, mouse muscular dystrophy (scid-mdx) mice, pericyte-derived cells colonize host muscle and generate numerous fibres expressing human dystrophin. Similar cells isolated from Duchenne patients, and engineered to express human mini-dystrophin, also give rise to many dystrophin-positive fibres in vivo. These data show that myogenic precursors, distinct from satellite cells, are associated with microvascular walls in the human skeletal muscle, may represent a correlate of embryonic 'mesoangioblasts' present after birth and may be a promising candidate for future cell-therapy protocols in patients.
961 citations
TL;DR: It is probably safe to counsel athletes with suspected myopathy to continue to undertake physical activity at a lower intensity, so as to prevent muscle damage from high intensity exercise and allow ample recovery to favour adequate recovery.
Abstract: Areas of general agreement: Total creatine kinase (CK) levels depend on age, gender, race, muscle mass, physical activity and climatic condition. High levels of serum CK in apparently healthy subjects may be correlated with physical training status, as they depend on sarcomeric damage: strenuous exercise that damages skeletal muscle cells results in increased total serum CK. The highest postexercise serum enzyme activities are found after prolonged exercise such as ultradistance marathon running or weight-bearing exercises and downhill running, which include eccentric muscular contractions. Total serum CK activity is markedly elevated for 24 h after the exercise bout and, when patients rest, it gradually returns to basal levels. Persistently increased serum CK levels are occasionally encountered in healthy individuals and are also markedly increased in the pre-clinical stages of muscle diseases. Areas that are controversial: Some authors, studying subjects with high levels of CK at rest, observed that, years later, subjects developed muscle weakness and suggested that early myopathy may be asymptomatic. Others demonstrated that, in most of these patients, hyperCKemia probably does not imply disease. In many instances, the diagnosis is not formulated following routine examination with the patients at rest, as symptoms become manifest only after exercise. Some authors think that strength training seems to be safe for patients with myopathy, even though the evidence for routine exercise prescription is still insufficient. Others believe that, in these conditions, intense prolonged exercise may produce negative effects, as it does not induce the physiological muscle adaptations to physical training given the continuous loss of muscle proteins. Growing points: High CK serum levels in athletes following absolute rest and without any further predisposing factors should prompt a full diagnostic workup with special regards to signs of muscle weakness or other simple signs that, in both athletes and sedentary subjects, are not always promptly evident. These signs may indicate subclinical muscle disease, which training loads may evidence through the onset of profound fatigue. It is probably safe to counsel athletes with suspected myopathy to continue to undertake physical activity at a lower intensity, so as to prevent muscle damage from high intensity exercise and allow ample recovery to favour adequate recovery.
777 citations
TL;DR: A randomized controlled trial of nonpharmacologic Interventions in the Elderly and the Canadian Consensus Conference on Non-Pharmacological Approaches to the Management of High Blood Pressure, Mar. 21-23, 1989, Halifax, Nova Scotia found that non-pharmacological approaches to the management of high blood pressure and weight loss were effective in older persons.
Abstract: 1. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low density lipoprotein cholesterol: a randomized controlled trial. JAMA. 2006;296:2563-2571. 2. Naylor CD. Clinical decisions: from art to science and back again. Lancet. 2001; 358:523-524. 3. Whelton PK, Appel LJ, Espeland MA, et al; TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled Trial of Nonpharmacologic Interventions in the Elderly (TONE). JAMA. 1998;279:839-846. 4. Chockalingam A, Abbott D, Bass M, et al. Recommendations of the Canadian Consensus Conference on Non-Pharmacological Approaches to the Management of High Blood Pressure, Mar. 21-23, 1989, Halifax, Nova Scotia. CMAJ. 1990; 142:1397-1409. 5. Mayer O Jr, Simon J, Heidrich J, Cokkinos DV, De Bacquer D; EUROASPIRE II Study Group. Educational level and risk profile of cardiac patients in the EUROASPIRE II substudy. J Epidemiol Community Health. 2004;58:47-52.
726 citations
TL;DR: The present review focuses on muscle-derived cytokines, their regulation by exercise, and their possible roles in metabolism and skeletal muscle function and it discusses which cytokines should be classified as true myokines.
Abstract: During the past 20 yr, it has been well documented that exercise has a profound effect on the immune system. With the discovery that exercise provokes an increase in a number of cytokines, a possible link between skeletal muscle contractile activity and immune changes was established. For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an "exercise factor," which could mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We suggest that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert either paracrine or endocrine effects should be classified as "myokines." Since the discovery of interleukin (IL)-6 release from contracting skeletal muscle, evidence has accumulated that supports an effect of IL-6 on metabolism. We suggested that muscle-derived IL-6 fulfils the criteria of an exercise factor and that such classes of cytokines should be named "myokines." Interestingly, recent research demonstrates that skeletal muscles can produce and express cytokines belonging to distinctly different families. Thus skeletal muscle has the capacity to express several myokines. To date the list includes IL-6, IL-8, and IL-15, and contractile activity plays a role in regulating the expression of these cytokines in skeletal muscle. The present review focuses on muscle-derived cytokines, their regulation by exercise, and their possible roles in metabolism and skeletal muscle function and it discusses which cytokines should be classified as true myokines.
700 citations
TL;DR: It is shown that increased TGF-β activity leads to failed muscle regeneration in fibrillin-1–deficient mice and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.
Abstract: Skeletal muscle has the ability to achieve rapid repair in response to injury or disease Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs 2,3) TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy
653 citations
TL;DR: In this article, the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle were investigated. But the results of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein.
Abstract: Skeletal muscle is a malleable tissue capable of altering the type and amount of protein in response to disruptions to cellular homeostasis The process of exercise-induced adaptation in skeletal muscle involves a multitude of signalling mechanisms initiating replication of specific DNA genetic sequences, enabling subsequent translation of the genetic message and ultimately generating a series of amino acids that form new proteins The functional consequences of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein Moreover, many features of the training adaptation are specific to the type of stimulus, such as the mode of exercise Prolonged endurance training elicits a variety of metabolic and morphological changes, including mitochondrial biogenesis, fast-to-slow fibre-type transformation and substrate metabolism In contrast, heavy resistance exercise stimulates synthesis of contractile proteins responsible for muscle hypertrophy and increases in maximal contractile force output Concomitant with the vastly different functional outcomes induced by these diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct With recent advances in technology, it is now possible to study the effects of various training interventions on a variety of signalling proteins and early-response genes in skeletal muscle Although it cannot presently be claimed that such scientific endeavours have influenced the training practices of elite athletes, these new and exciting technologies have provided insight into how current training techniques result in specific muscular adaptations, and may ultimately provide clues for future and novel training methodologies Greater knowledge of the mechanisms and interaction of exercise-induced adaptive pathways in skeletal muscle is important for our understanding of the aetiology of disease, maintenance of metabolic and functional capacity with aging, and training for athletic performance This article highlights the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle
TL;DR: In this paper, the authors examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of post-prandial energy storage.
Abstract: We examined the hypothesis that insulin resistance in skeletal muscle promotes the development of atherogenic dyslipidemia, associated with the metabolic syndrome, by altering the distribution pattern of postprandial energy storage. Following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by ≈60% in young, lean, insulin-resistant subjects compared with a similar cohort of age–weight–body mass index–activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an ≈20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-α, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-α, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intraabdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome.
TL;DR: The mechanism by which MYH is depleted under atrophy conditions is identified and it is demonstrated that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.
TL;DR: In older adults, type 2 diabetes is associated with accelerated loss of leg muscle strength and quality, and these declines were attenuated but remained significant after controlling for demographics, body composition, physical activity, combined chronic diseases, interleukin-6, and tumor necrosis factor-α.
Abstract: OBJECTIVE —It has been shown that adults with either long-standing type 1 or type 2 diabetes had lower skeletal muscle strength than nondiabetic adults in cross-sectional studies. The aim of the study was to investigate longitudinal changes of muscle mass and strength in community-dwelling older adults with and without type 2 diabetes.
RESEARCH DESIGN AND METHODS —We examined leg and arm muscle mass and strength at baseline and 3 years later in 1,840 older adults aged 70–79 years in the Health, Aging, and Body Composition Study. Regional muscle mass was measured by dual energy X-ray absorptiometry, and muscle strength was measured using isokinetic and isometric dynamometers.
RESULTS —Older adults with type 2 diabetes ( n = 305) showed greater declines in the leg muscle mass (−0.29 ± 0.03 vs. −0.23 ± 0.01 kg, P < 0.05) and strength (−16.5 ± 1.2 vs. −12.4 ± 0.5 Nm, P = 0.001) compared with older adults without diabetes. Leg muscle quality, expressed as maximal strength per unit of muscle mass (Newton meters per kilogram), also declined more rapidly in older adults with diabetes (−1.6 ± 0.2 vs. −1.2 ± 0.1 Nm/kg, P < 0.05). Changes in arm muscle strength and quality were not different between those with and without diabetes. Rapid declines in leg muscle strength and quality were attenuated but remained significant after controlling for demographics, body composition, physical activity, combined chronic diseases, interleukin-6, and tumor necrosis factor-α.
CONCLUSIONS —In older adults, type 2 diabetes is associated with accelerated loss of leg muscle strength and quality.
TL;DR: A critical role is demonstrated for PGC-1α in maintenance of normal fiber type composition and of muscle fiber integrity following exertion in skeletal muscle knock-out animals.
TL;DR: In this paper, a 35-day high-intensity resistance training (RT) program was used to assess the early changes in muscle size and architecture during a bilateral leg extension three times per week on a gravity-independent flywheel ergometer.
Abstract: The onset of whole muscle hypertrophy in response to overloading is poorly documented. The purpose of this study was to assess the early changes in muscle size and architecture during a 35-day high-intensity resistance training (RT) program. Seven young healthy volunteers performed bilateral leg extension three times per week on a gravity-independent flywheel ergometer. Cross-sectional area (CSA) in the central (C) and distal (D) regions of the quadriceps femoris (QF), muscle architecture, maximal voluntary contraction (MVC), and electromyographic (EMG) activity were measured before and after 10, 20, and 35 days of RT. By the end of the training period, MVC and EMG activity increased by 38.9 ± 5.7 and 34.8% ± 4.7%, respectively. Significant increase in QF CSA (3.5 and 5.2% in the C and D regions, respectively) was observed after 20 days of training, along with a 2.4 ± 0.7% increase in fascicle length from the 10th day of training. By the end of the 35-day training period, the total increase in QF CSA for regions C and D was 6.5 ± 1.1 and 7.4 ± 0.8%, respectively, and fascicle length and pennation angle increased by 9.9 ± 1.2 and 7.7 ± 1.3%, respectively. The results show for the first time that changes in muscle size are detectable after only 3 wk of RT and that remodeling of muscle architecture precedes gains in muscle CSA. Muscle hypertrophy seems to contribute to strength gains earlier than previously reported; flywheel training seems particularly effective for inducing these early structural adaptations.
TL;DR: Evidence is provided for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle oftype 2 diabetic patients that may contribute to the development of type 1 diabetes in humans with obesity.
Abstract: We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-l-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity.
TL;DR: It is suggested that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.
Abstract: A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including 14C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, β-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet–fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1α, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.
TL;DR: The myogenic potential of satellite cells is under the molecular control of specific paired-box and bHLH transcription factors whose tightly orchestrated balance accounts for an effective skeletal muscle regeneration.
TL;DR: It appears that activation of PGC-1α may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in P GC-1 α protein sustains and enhances the increase in mitochondrial biogenesis.
TL;DR: The key clinical question is whether changes in body composition are distinct entities or represent an interdependent continuum and the importance of defining the distinction lies in developing a targeted therapeutic approach to skeletal muscle loss and muscle strength in older persons.
TL;DR: Findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
Abstract: PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
TL;DR: Testing the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content found no differences between patients with type 2 diabetes and healthy control subjects.
Abstract: Aims/hypothesis
Insulin resistance and type 2 diabetes are associated with mitochondrial dysfunction. The aim of the present study was to test the hypothesis that oxidative phosphorylation and electron transport capacity are diminished in the skeletal muscle of type 2 diabetic subjects, as a result of a reduction in the mitochondrial content.
TL;DR: The timing of the gene induction indicated early elevation of proteolytic genes, followed by prolonged elevation of cytokines and suppression of myostatin during and after an acute bout of resistance (RE) or run (RUN) exercise.
Abstract: The aim of this study was to examine the time course induction of select proteolytic [muscle ring finger-1 (MuRF-1), atrogin-1, forkhead box 3A (FOXO3A), calpain-1, calpain-2], myostatin, and cytok...
TL;DR: An overview of muscle proteases, outline intracellular sources of reactive oxygen species, and summarize the evidence that connects oxidative stress to signaling pathways contributing to disuse muscle atrophy are provided.
Abstract: Skeletal muscle inactivity is associated with a loss of muscle protein and reduced force-generating capacity. This disuse-induced muscle atrophy results from both increased proteolysis and decreased protein synthesis. Investigations of the cell signaling pathways that regulate disuse muscle atrophy have increased our understanding of this complex process. Emerging evidence implicates oxidative stress as a key regulator of cell signaling pathways, leading to increased proteolysis and muscle atrophy during periods of prolonged disuse. This review will discuss the role of reactive oxygen species in the regulation of inactivity-induced skeletal muscle atrophy. The specific objectives of this article are to provide an overview of muscle proteases, outline intracellular sources of reactive oxygen species, and summarize the evidence that connects oxidative stress to signaling pathways contributing to disuse muscle atrophy. Moreover, this review will also discuss the specific role that oxidative stress plays in signaling pathways responsible for muscle proteolysis and myonuclear apoptosis and highlight gaps in our knowledge of disuse muscle atrophy. By presenting unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.
TL;DR: The data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM, as it regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle.
Abstract: Background Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.
TL;DR: The hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial oxidative phosphorylation is supported.
Abstract: Insulin resistance is the best predictor for the development of diabetes in offspring of type 2 diabetic patients, but the mechanism responsible for it remains unknown. Recent studies have demonstrated increased intramyocellular lipid, decreased mitochondrial ATP synthesis, and decreased mitochondrial density in the muscle of lean, insulin-resistant offspring of type 2 diabetic patients. These data suggest an important role for mitochondrial dysfunction in the pathogenesis of type 2 diabetes. To further explore this hypothesis, we assessed rates of substrate oxidation in the muscle of these same individuals using 13C magnetic resonance spectroscopy (MRS). Young, lean, insulin-resistant offspring of type 2 diabetic patients and insulin-sensitive control subjects underwent 13C MRS studies to noninvasively assess rates of substrate oxidation in muscle by monitoring the incorporation of 13C label into C4 glutamate during a [2-13C]acetate infusion. Using this approach, we found that rates of muscle mitochondrial substrate oxidation were decreased by 30% in lean, insulin-resistant offspring (59.8 ± 5.1 nmol · g−1 · min−1, P = 0.02) compared with insulin-sensitive control subjects (96.1 ± 16.3 nmol · g−1 · min−1). These data support the hypothesis that insulin resistance in skeletal muscle of insulin-resistant offspring is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in the activity of mitochondrial oxidative phosphorylation.
TL;DR: Gene set enrichment analysis revealed that quiescent satellite cells preferentially express the genes involved in cell‐cell adhesion, regulation of cell growth, formation of extracellular matrix, copper and iron homeostasis, and lipid transportation, and calcitonin receptor was exclusively expressed in dormant satellite cells but not in activated satellite cells.
Abstract: Skeletal muscle satellite cells play key roles in postnatal muscle growth and regeneration. To study molecular regulation of satellite cells, we directly prepared satellite cells from 8- to 12-week-old C57BL/6 mice and performed genome-wide gene expression analysis. Compared with activated/cycling satellite cells, 507 genes were highly upregulated in quiescent satellite cells. These included negative regulators of cell cycle and myogenic inhibitors. Gene set enrichment analysis revealed that quiescent satellite cells preferentially express the genes involved in cell-cell adhesion, regulation of cell growth, formation of extracellular matrix, copper and iron homeostasis, and lipid transportation. Furthermore, reverse transcription-polymerase chain reaction on differentially expressed genes confirmed that calcitonin receptor (CTR) was exclusively expressed in dormant satellite cells but not in activated satellite cells. In addition, CTR mRNA is hardly detected in nonmyogenic cells. Therefore, we next examined the expression of CTR in vivo. CTR was specifically expressed on quiescent satellite cells, but the expression was not found on activated/proliferating satellite cells during muscle regeneration. CTR-positive cells reappeared at the rim of regenerating myofibers in later stages of muscle regeneration. Calcitonin stimulation delayed the activation of quiescent satellite cells. Our data provide roles of CTR in quiescent satellite cells and a solid scaffold to further dissect molecular regulation of satellite cells. Disclosure of potential conflicts of interest is found at the end of this article.
TL;DR: It is suggested that the IKK/NF-kappaB signaling pathway as a potential therapeutic target for DMD and specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice.
Abstract: Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-kappaB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKbeta in mdx mice elucidated that NF-kappaB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-kappaB in the progression of muscular dystrophy and suggest the IKK/NF-kappaB signaling pathway as a potential therapeutic target for DMD.
TL;DR: This study is the first to show type II fiber atrophy in the elderly to be associated with a fiber type-specific decline in SC content, which is evident when SC content is expressed per fiber or per fiber area.
Abstract: Satellite cells (SC) are essential for skeletal muscle growth and repair. Because sarcopenia is associated with type II muscle fiber atrophy, we hypothesized that SC content is specifically reduced in the type II fibers in the elderly. A total of eight elderly (E; 76 +/- 1 yr) and eight young (Y; 20 +/- 1 yr) healthy males were selected. Muscle biopsies were collected from the vastus lateralis in both legs. ATPase staining and a pax7-antibody were used to determine fiber type-specific SC content (i.e., pax7-positive SC) on serial muscle cross sections. In contrast to the type I fibers, the proportion and mean cross-sectional area of the type II fibers were substantially reduced in E vs. Y. The number of SC per type I fiber was similar in E and Y. However, the number of SC per type II fiber was substantially lower in E vs. Y (0.044 +/- 0.003 vs. 0.080 +/- 0.007; P < 0.01). In addition, in the type II fibers, the number of SC relative to the total number of nuclei and the number of SC per fiber area were also significantly lower in E. This study is the first to show type II fiber atrophy in the elderly to be associated with a fiber type-specific decline in SC content. The latter is evident when SC content is expressed per fiber or per fiber area. The decline in SC content might be an important factor in the etiology of type II muscle fiber atrophy, which accompanies the loss of skeletal muscle with aging.