Periods Of Disuse Research Articles

Disuse Impairs the Muscle Protein Synthetic Response to Protein Ingestion in Healthy Men

Disuse leads to rapid skeletal muscle atrophy, which brings about numerous negative health consequences. Muscle disuse atrophy is, at least in part, attributed to a decline in basal (postabsorptive) muscle protein synthesis rates. However, it remains to be determined whether muscle disuse also impairs the muscle protein synthetic response to dietary protein ingestion. We assessed muscle protein synthesis rates after protein ingestion before and after a period of disuse in humans. Twelve healthy young (24 ± 1 year) men underwent a 14-day period of one-legged knee immobilization by way of a full leg cast. Before and after the immobilization period, quadriceps cross-sectional area, muscle strength, skeletal muscle protein synthesis rates, and associated im (intramuscular) molecular signaling were assessed. Continuous infusions of l-[ring-²H₅]phenylalanine were applied to assess mixed-muscle protein fractional synthetic rates after the ingestion of 20 g dietary protein. Immobilization led to an 8.4% ± 2.8% (P < .001) and 22.9% ± 2.6% (P < .001) decrease in quadriceps muscle cross-sectional area and strength, respectively. Immobilization resulted in a 31% ± 12% reduction in postprandial muscle protein synthesis rates (from 0.046% ± 0.004% to 0.032% ± 0.006% per hour; P < .05). These findings were observed without any discernible changes in the skeletal muscle phosphorylation status of mammalian target of rapamycin or p70 ribosomal protein S6 kinase. A short period of muscle disuse impairs the muscle protein synthetic response to dietary protein intake in vivo in healthy young men. Thus, anabolic resistance to protein ingestion contributes significantly to the loss of muscle mass that is observed during disuse.

The Use of Chemostats in Microbial Systems Biology

Cells regulate their rate of growth in response to signals from the external world. As the cell grows, diverse cellular processes must be coordinated including macromolecular synthesis, metabolism and ultimately, commitment to the cell division cycle. The chemostat, a method of experimentally controlling cell growth rate, provides a powerful means of systematically studying how growth rate impacts cellular processes - including gene expression and metabolism - and the regulatory networks that control the rate of cell growth. When maintained for hundreds of generations chemostats can be used to study adaptive evolution of microbes in environmental conditions that limit cell growth. We describe the principle of chemostat cultures, demonstrate their operation and provide examples of their various applications. Following a period of disuse after their introduction in the middle of the twentieth century, the convergence of genome-scale methodologies with a renewed interest in the regulation of cell growth and the molecular basis of adaptive evolution is stimulating a renaissance in the use of chemostats in biological research.

The Use of Chemostats in Microbial Systems Biology

Cells regulate their rate of growth in response to signals from the external world. As the cell grows, diverse cellular processes must be coordinated including macromolecular synthesis, metabolism and ultimately, commitment to the cell division cycle. The chemostat, a method of experimentally controlling cell growth rate, provides a powerful means of systematically studying how growth rate impacts cellular processes - including gene expression and metabolism - and the regulatory networks that control the rate of cell growth. When maintained for hundreds of generations chemostats can be used to study adaptive evolution of microbes in environmental conditions that limit cell growth. We describe the principle of chemostat cultures, demonstrate their operation and provide examples of their various applications. Following a period of disuse after their introduction in the middle of the twentieth century, the convergence of genome-scale methodologies with a renewed interest in the regulation of cell growth and the molecular basis of adaptive evolution is stimulating a renaissance in the use of chemostats in biological research.

Nutritional strategies to counteract muscle atrophy caused by disuse and to improve recovery

Periods of immobilisation are often associated with pathologies and/or ageing. These periods of muscle disuse induce muscle atrophy which could worsen the pathology or elderly frailty. If muscle mass loss has positive effects in the short term, a sustained/uncontrolled muscle mass loss is deleterious for health. Muscle mass recovery following immobilisation-induced atrophy could be critical, particularly when it is uncompleted as observed during ageing. Exercise, the best way to recover muscle mass, is not always applicable. So, other approaches such as nutritional strategies are needed to limit muscle wasting and to improve muscle mass recovery in such situations. The present review discusses mechanisms involved in muscle atrophy following disuse and during recovery and emphasises the effect of age in these mechanisms. In addition, the efficiency of nutritional strategies proposed to limit muscle mass loss during disuse and to improve protein gain during recovery (leucine supplementation, whey proteins, antioxidants and anti-inflammatory compounds, energy intake) is also discussed.

β-Hydroxy-β-methylbutyrate (HMB) enhances the proliferation of satellite cells in fast muscles of aged rats during recovery from disuse atrophy

Loss of myonuclei by apoptosis is thought to contribute to sarcopenia. We have previously shown, that the leucine metabolite, β-hydroxy-β-methylbutyrate (HMB) suppresses apoptotic signaling and the apoptotic index (the ratio of apoptotic positive to apoptotic negative myonuclei) during muscle disuse and during reloading periods after disuse in aged rats. However, it was not clear if the apoptotic signaling indexes were due only to preservation of myonuclei or if perhaps the total myogenic pool increased as a result of HMB-mediated satellite cell proliferation as this would have also reduced the apoptotic index. In this study, we tested the hypothesis that HMB would augment myogenic cells (satellite cells) proliferation during muscle recovery (growth) after a period of disuse in senescent animals. The hindlimb muscles of 34month old Fisher 344×Brown Norway rats were unloaded for 14days by hindlimb suspension (HLS), and then reloaded for 14days. The rats received either Ca-HMB (340mg/kg body weight; n=16), or the vehicle (n=10) by gavage throughout the experimental period. HMB prevented the functional decline in maximal plantar flexion isometric force production during the reloading period, but not during HLS. HMB-treatment enhanced the proliferation of muscle stem cells as shown by a greater percentage of satellite cells that had proliferated (more BrdU positive, Pax-7 positive, and more Pax7/Ki67 positive nuclei) and as a result, more differentiated stem cells were present (more MyoD/myogenin positive myonuclei), relative to total myonuclei, in reloaded plantaris muscles as compared to reloaded muscles from vehicle-treated animals. Furthermore HMB increased the nuclear protein abundance of proliferation markers, inhibitor of differentiation-2 and cyclin A, as compared to vehicle treatment in reloaded muscles. Although HMB increased phosphorylated Akt during reloading, other mTOR related proteins were not altered by HMB treatment. These data show that HMB improved the proliferation of muscle stem cells in fast twitch plantaris muscles. Enhanced satellite cell proliferation leading to increased differentiated myonuclei should increase the transcriptional potential to support muscle hypertrophic changes and functional changes in sarcopenic muscles, and this could partly explain the reduced apoptotic index in HMB treated muscles. Indeed, muscle mass and fiber cross-sectional area were significantly greater in plantaris muscles from HMB-treated animal muscles after reloading as compared to vehicle-treated animals.

Black Bears With Longer Disuse (Hibernation) Periods Have Lower Femoral Osteon Population Density and Greater Mineralization and Intracortical Porosity

Intracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age-related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25-7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age-related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse- or age-related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age- and disuse-related osteoporoses in humans.

A Portrait of Abe no Seimei

Abe no Seimei is one of the most famous figures in the history of Onmyodo, with many tales attached to his name that attribute to him special powers and accomplishments. This article looks at the historical records concerning Abe no Seimei and tries to reconstruct what can be known historically of his life and actions. The records show that Abe no Seimei did not reach prominence and a high rank until late in his life, well over sixty years of age. The article concludes that if the onmyoji Abe no Seimei had not lived a long life, he probably would not have achieved the unusual fame that developed in later periods.KEYWORDS: Abe no Seimei-henbai-demons-onmyoji-ritsuryo code-shikigami-festival rituals(ProQuest: ... denotes non-US-ASCII text omitted.)During the time that Abe no Seimei ... (921-1005)1 was active, there was a nobleman, Fujiwara no Yukinari ... (972-1027), who was one of the three outstanding calligraphers of his day. We know from his diary, Gonki ... (Choho 2 [1000].10.11.), that Seimei was regarded at the time as the practitioner of Onmyodo (michi no kesshutsusha ...).On the eleventh day of the tenth month of Ch.ho 2, the reconstruction of the Imperial Palace, which had previously been destroyed in a fire, was finally completed. On that day, Emperor Ichij. (980.1011, r. 986.1011) moved from his temporary residence into the new palace building, at which time Seimei performed the magical step called henbai ... According to Yukinari, this was the first time henbai had been performed on such an occasion. Formerly when the had entered a new palace, a ritual act involving the scattering of uncooked grains of rice (sangu ...) had been made, a rite that came under the purview of the Onmy.ry. ... (Bureau of Yin and Yang), the government office in charge of divination, calendars, astrology, and time-keeping. So in 1000, Abe no Seimei not only performed a rite different from precedent, but it was done by someone who was not an officer of the Onmy.ry.. As to why this was permitted, Yukinari wrote, was because Seimei was the preeminent practitioner of (onmy.)d. that he attended on the emperor (Gonki, Ch.h. 2.10.11).The henbai that Seimei performed on that occasion was a series of special steps used to tread the ground accompanied by incantations. An example of its use prior to 1000 appears in the diary of Taira no Chikanobu ... (945.1017), Chikanobu-ky. ki, in an item dated Ten'en 2 (974).2.9. A prominent onmyoji ... called Kamo no Yasunori ... performed henbai on behalf of Minamoto no Michisato ... who was leaving for the province of Sanuki to which he had been appointed Provisional Assistant Governor. It is easy to imagine that this was done to ensure him safety on the road. For people of the time, henbai seems to have been a magical device to guarantee personal safety when going to an unknown place or a place perceived as dangerous.2Thus, it was not strange that henbai should have been used when the was moving into a new palace. A new residence truly was an unknown space. In fact, the nobility of the time would not have occupied a newly-built dwelling until a complex series of rites focusing on the new building, including the performance of henbai by onmyoji, had been undertaken. For example, Fujiwara no Michinaga ... notes in his diary Midokanpakuki, in an entry dated Kanko 2 (1005).2.10, that he had waited for Abe no Seimei at the gate of his new residence. It seems that Seimei, who was supposed to perform the rites for the newly-built mansion, was somewhat late in arriving.3Several tales in the twenty-seventh fascicle (Honcho reikibu) of the Konjaku monogatari shu suggest that people in the Heian period considered not just new dwellings but any kind of house as a potentially dangerous space occupied by spirits and demons. Even when the nobility began using a residence after a period of disuse, they would have an onmyoji perform henbai before occupying it again. …

Loss of the Inducible Hsp70 Delays the Inflammatory Response to Skeletal Muscle Injury and Severely Impairs Muscle Regeneration

Skeletal muscle regeneration following injury is a highly coordinated process that involves transient muscle inflammation, removal of necrotic cellular debris and subsequent replacement of damaged myofibers through secondary myogenesis. However, the molecular mechanisms which coordinate these events are only beginning to be defined. In the current study we demonstrate that Heat shock protein 70 (Hsp70) is increased following muscle injury, and is necessary for the normal sequence of events following severe injury induced by cardiotoxin, and physiological injury induced by modified muscle use. Indeed, Hsp70 ablated mice showed a significantly delayed inflammatory response to muscle injury induced by cardiotoxin, with nearly undetected levels of both neutrophil and macrophage markers 24 hours post-injury. At later time points, Hsp70 ablated mice showed sustained muscle inflammation and necrosis, calcium deposition and impaired fiber regeneration that persisted several weeks post-injury. Through rescue experiments reintroducing Hsp70 intracellular expression plasmids into muscles of Hsp70 ablated mice either prior to injury or post-injury, we confirm that Hsp70 optimally promotes muscle regeneration when expressed during both the inflammatory phase that predominates in the first four days following severe injury and the regenerative phase that predominates thereafter. Additional rescue experiments reintroducing Hsp70 protein into the extracellular microenvironment of injured muscles at the onset of injury provides further evidence that Hsp70 released from damaged muscle may drive the early inflammatory response to injury. Importantly, following induction of physiological injury through muscle reloading following a period of muscle disuse, reduced inflammation in 3-day reloaded muscles of Hsp70 ablated mice was associated with preservation of myofibers, and increased muscle force production at later time points compared to WT. Collectively our findings indicate that depending on the nature and severity of muscle injury, therapeutics which differentially target both intracellular and extracellular localized Hsp70 may optimally preserve muscle tissue and promote muscle functional recovery.

Two Weeks of Reduced Activity Decreases Leg Lean Mass and Induces “Anabolic Resistance” of Myofibrillar Protein Synthesis in Healthy Elderly

Alterations in muscle protein metabolism underlie age-related muscle atrophy. During periods of muscle disuse, muscle protein synthesis is blunted, and muscle atrophy occurs in young and old. The impact of a short reduction in physical activity on muscle protein metabolism in older adults is unknown. The aim of this study was to investigate the impact of 14 days of reduced daily steps on fasted and fed-state rates of myofibrillar protein synthesis (MPS) to provide insight into the mechanisms for changes in muscle mass and markers of metabolic health. Before and after 14 days of reduced daily step-count, 10 healthy older adults (age, 72 ± 1 y) underwent measures of insulin sensitivity, muscle strength, physical function, and body composition. Using a primed constant infusion of L-[ring-(13)C6]phenylalanine with serial muscle biopsies, basal, postabsorptive, and postprandial rates of MPS were determined before and after the 14-day intervention. Daily step-count was reduced by approximately 76% to 1413 ± 110 steps per day. Leg fat-free mass was reduced by approximately 3.9% (P < .001). Postabsorptive insulin resistance was increased by approximately 12%, and postprandial insulin sensitivity was reduced by approximately 43% after step reduction (P < .005). Concentrations of TNF-α and C-reactive protein were increased by approximately 12 and 25%, respectively, after step reduction (P < .05). Postprandial rates of MPS were reduced by approximately 26% after the intervention (P = .028), with no difference in postabsorptive rates. The present study demonstrates that 14 days of reduced steps in older adults induces small but measurable reductions in muscle mass that appear to be underpinned by reductions in postprandial MPS and are accompanied by impairments in insulin sensitivity and systemic inflammatory markers and postprandial MPS.

Nutritional strategies to attenuate muscle disuse atrophy

Situations such as recovery from injury or illness require otherwise healthy humans to undergo periods of disuse, which lead to considerable losses of skeletal muscle mass and, subsequently, numerous negative health consequences. It has been established that prolonged disuse (>10 days) leads to a decline in basal and postprandial rates of muscle protein synthesis, without an apparent change in muscle protein breakdown. It also seems, however, that an early and transient (1-5 days) increase in basal muscle protein breakdown may also contribute to disuse atrophy. A period of disuse reduces energy requirements and appetite. Consequently, food intake generally declines, resulting in an inadequate dietary protein consumption to allow proper muscle mass maintenance. Evidence suggests that maintaining protein intake during a period of disuse attenuates disuse atrophy. Furthermore, supplementation with dietary protein and/or essential amino acids can be applied to further aid in muscle mass preservation during disuse. Such strategies are of particular relevance to the older patient at risk of developing sarcopenia. More work is required to elucidate the impact of disuse on basal and postprandial rates of muscle protein synthesis and breakdown. Such information will provide novel targets for nutritional interventions to further attenuate muscle disuse atrophy and, as such, support healthy aging.

Philosophical &lt;i&gt;Parrêsia&lt;/i&gt; and Transpolitical Freedom

This article highlights that ancient philosophy regenerated the practice of parrêsia following the crisis into which it had fallen in the polis. Through this, it established a strong relationship between freedom, truth, and politics, constantly eluding the risk of using “true speech” as a tool of rationalizing the exercise of power. The primary outset for the argument will be the course held by Foucault in 1982-1983 (Le gouvernement de soi et des autres). The paper holds that philosophical parrêsia asserted itself as a practice that could not be anything but “transpolitical,” while remaining similar to the ideal of freedom as active participation in public life – at least in the case of Socrates and the Cynics. According to Foucault, after a long period of disuse due to the predominance of theology and pastoral power, philosophical parrêsia was able to flourish in modernity. This occurred above all with Kant through the critical ontology of the present. On my part, I try to show how philosophical parrêsia in liberal society runs the risk of being neutralized by the predominance of economic “true speech” and by the prevalence of the idea of freedom as the pursuit of private interests. This is done by re-reading certain indications provided by Foucault himself in his course of 1978-1979 (Naissance de la biopolitique). Moreover, in the last sections of this paper I suggest lines of research that could grasp the difficulties that philosophical parrêsia encounters in the age of neoliberal hegemony and global media coverage.

Severe burn and disuse in the rat independently adversely impact body composition and adipokines

IntroductionSevere trauma is accompanied by a period of hypermetabolism and disuse. In this study, a rat model was used to determine the effects of burn and disuse independently and in combination on body composition, food intake and adipokines.MethodsMale rats were assigned to four groups 1) sham ambulatory (SA), 2) sham hindlimb unloaded (SH), 3) 40% total body surface area full thickness scald burn ambulatory (BA) and 4) burn and hindlimb unloaded (BH). Animals designated to the SH and BH groups were placed in a tail traction system and their hindlimbs unloaded. Animals were followed for 14 days. Plasma, urine, fecal and tissue samples were analyzed.ResultsSA had a progressive increase in body mass (BM), SH and BA no change and BH a reduction. Compared to SA, BM was reduced by 10% in both SH and BA and by 17% when combined in BH. Compared to SA, all groups had reductions in lean and fat body mass with BH being greater. The decrease in lean mass was associated with the rate of urinary corticosterone excretion. The loss in fat mass was associated with decreases in plasma leptin and adiponectin and an increase in ghrelin. Following the acute response to injury, BH had a greater food intake per 100 g BM. Food intake was associated with the levels of leptin, adiponectin and ghrelin.ConclusionsThe effects of the combination of burn and disuse in this animal model were additive, therefore in assessing metabolic changes with severe trauma both injury and disuse should be considered. Furthermore, the observed changes in adipokines, corticosterone and ghrelin provide insights for interventions to attenuate the hypermetabolic state following injury, possibly reducing catabolism and muscle loss and subsequent adverse effects on recovery and function.

Aging Affects the Transcriptional Regulation of Human Skeletal Muscle Disuse Atrophy

Important insights concerning the molecular basis of skeletal muscle disuse-atrophy and aging related muscle loss have been obtained in cell culture and animal models, but these regulatory signaling pathways have not previously been studied in aging human muscle. In the present study, muscle atrophy was induced by immobilization in healthy old and young individuals to study the time-course and transcriptional factors underlying human skeletal muscle atrophy. The results reveal that irrespectively of age, mRNA expression levels of MuRF-1 and Atrogin-1 increased in the very initial phase (2–4 days) of human disuse-muscle atrophy along with a marked reduction in PGC-1α and PGC-1β (1–4 days) and a ∼10% decrease in myofiber size (4 days). Further, an age-specific decrease in Akt and S6 phosphorylation was observed in young muscle within the first days (1–4 days) of immobilization. In contrast, Akt phosphorylation was unchanged in old muscle after 2 days and increased after 4 days of immobilization. Further, an age-specific down-regulation of MuRF-1 and Atrogin-1 expression levels was observed following 2 weeks of immobilization, along with a slowing atrophy response in aged skeletal muscle. Neither the immediate loss of muscle mass, nor the subsequent age-differentiated signaling responses could be explained by changes in inflammatory mediators, apoptosis markers or autophagy indicators. Collectively, these findings indicate that the time-course and regulation of human skeletal muscle atrophy is age dependent, leading to an attenuated loss in aging skeletal muscle when exposed to longer periods of immobility-induced disuse.

Therapeutic Strategies that Target Epigenetic, Paracrine and Signalling Control of Skeletal Muscle Regeneration

Skeletal muscle is highly efficient at self-repair following injury via a complex interplay of muscle and nonmuscle cellular components, soluble growth factors, and the extracellular matrix. Under certain circumstances, such as after extensive acute tissue injury, prolonged periods of muscle disuse, and in some diseases, the regenerative capacity of muscle can be overwhelmed or impaired. Predictive muscle break down can also occur (e.g., in age-related loss of muscle mass and function, and post-operatively when procedures involve direct muscle damage, denervation or loss of blood supply), and strategies that facilitate muscle regeneration and reduce recovery time or the effects of ageing would be highly beneficial. Thus, there is a need for therapeutic approaches that promote muscle regeneration after injury, and/or to preemptively protect muscles from damage. Recent research has culminated in a range of patents that focus on the therapeutic enhancement of skeletal muscle regeneration and/or protection of existing muscle mass. This paper reviews recent research developments and therapeutically-based patents and patent applications that target epigenetic, paracrine, and signalling mechanisms underlying the normal regeneration process. Keywords: Ageing, epigenetic, growth factor, muscular dystrophy, myogenesis, regeneration, skeletal muscle, signal transduction, MYOGENIC PROCESSES, myoblast proliferation.

Therapeutic Strategies that Target Epigenetic, Paracrine and Signalling Control of Skeletal Muscle Regeneration

Skeletal muscle is highly efficient at self-repair following injury via a complex interplay of muscle and nonmuscle cellular components, soluble growth factors, and the extracellular matrix. Under certain circumstances, such as after extensive acute tissue injury, prolonged periods of muscle disuse, and in some diseases, the regenerative capacity of muscle can be overwhelmed or impaired. Predictive muscle break down can also occur (e.g., in age-related loss of muscle mass and function, and post-operatively when procedures involve direct muscle damage, denervation or loss of blood supply), and strategies that facilitate muscle regeneration and reduce recovery time or the effects of ageing would be highly beneficial. Thus, there is a need for therapeutic approaches that promote muscle regeneration after injury, and/or to preemptively protect muscles from damage. Recent research has culminated in a range of patents that focus on the therapeutic enhancement of skeletal muscle regeneration and/or protection of existing muscle mass. This paper reviews recent research developments and therapeutically-based patents and patent applications that target epigenetic, paracrine, and signalling mechanisms underlying the normal regeneration process.

Neuromuscular electrical stimulation increases muscle protein synthesis in elderly type 2 diabetic men

Physical activity is required to attenuate the loss of skeletal muscle mass with aging. Short periods of muscle disuse, due to sickness or hospitalization, reduce muscle protein synthesis rates, resulting in rapid muscle loss. The present study investigates the capacity of neuromuscular electrical stimulation (NMES) to increase in vivo skeletal muscle protein synthesis rates in older type 2 diabetes patients. Six elderly type 2 diabetic men (70 ± 2 yr) were subjected to 60 min of one-legged NMES. Continuous infusions with L-[ring-¹³C₆]phenylalanine were applied, with blood and muscle samples being collected regularly to assess muscle protein synthesis rates in both the stimulated (STIM) and nonstimulated control (CON) leg during 4 h of recovery after NMES. Furthermore, mRNA expression of key genes implicated in the regulation of muscle mass were measured over time in the STIM and CON leg. Muscle protein synthesis rates were greater in the STIM compared with the CON leg during recovery from NMES (0.057 ± 0.008 vs. 0.045 ± 0.008%/h, respectively, P < 0.01). Skeletal muscle myostatin mRNA expression in the STIM leg tended to increase immediately following NMES compared with the CON leg (1.63- vs. 1.00-fold, respectively, P = 0.07) but strongly declined after 2 and 4 h of recovery in the STIM leg only. In conclusion, this is the first study to show that NMES directly stimulates skeletal muscle protein synthesis rates in vivo in humans. NMES likely represents an effective interventional strategy to attenuate muscle loss in elderly individuals during bed rest and/or in other disuse states.

Contributions to the understanding of the anabolic properties of different dietary proteins

Contributions to the understanding of the anabolic properties of different dietary proteins

Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1–84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.

Oxidative stress and disuse muscle atrophy

This review will discuss the evidence both for and against the concept that reactive oxygen species (ROS) play an important role in the regulation of inactivity-induced skeletal muscle atrophy. It is well established that prolonged skeletal muscle inactivity causes muscle fiber atrophy and a decrease in muscle force production. This disuse-induced muscle atrophy is the consequence of a loss in muscle protein resulting from increased protein degradation and decreased protein synthesis. Recent studies suggest that oxidative stress can influence cell-signaling pathways that regulate both muscle protein breakdown and synthesis during prolonged periods of disuse. Specifically, it is feasible that increased ROS production in muscle fibers can promote increased proteolysis and also depress protein synthesis during periods of skeletal muscle inactivity. Although it is established that oxidants can participate in the regulation of protein turnover in cells, there remains debate as to whether oxidative stress is required for disuse skeletal muscle atrophy. Nonetheless, based on emerging evidence we conclude that increased ROS production in skeletal muscles significantly contributes to inactivity-induced muscle atrophy.

Leucine: a nutrient 'trigger' for muscle anabolism, but what more?

Leucine: a nutrient 'trigger' for muscle anabolism, but what more?