Force and power output of fast and slow skeletal muscles from mdx mice 6-28 months old

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66165/1/j.1469-7793.2001.00591.x.pd

Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation

The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. m

Accountability, Strategy, and International Non-Governmental Organizations

Increased prominence and greater influence expose international non-governmental development and environmental organizations (INGOs) to increased demands for accountability from a wide variety of stakeholdersdonors, beneficiaries, staffs, and partners among others. This paper focuses on developing the concept of INGO accountability, first as an abstract concept and then as a strategic idea with very different implications for different INGO strategies. We examine those implications for INGOs that emphasize service delivery, capacity-building, and policy influence. We propose that INGOs committed to service delivery may owe more accountability to donors and service regulators; capacity-building INGOs may be particularly obligated to clients whose capacities are being enhanced; and policy influence INGOs may be especially accountable to political constituencies and to influence targets. INGOs that are expanding their activities to include new initiatives may need to reorganize their accountability systems to implement their strategies effectively. This publication is Hauser Center Working Paper No. 7. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers

The Concept of Transparency in International Relations: towards a critical approach

Transparency is an important concept in International Relations. The possibility of realizing transparency in practice operates as a central analytical axis defining distinct positions on core theoretical problems within the field, from the security dilemma to the function of international institutions and beyond. As a political practice the pursuit of transparent governance is a dominant feature of global politics, promoted by a wide range of actors across a vast range of issue areas, from nuclear proliferation to Internet governance to the politics of foreign aid. Yet, despite its importance, precisely what transparency means or how the concept is understood is frequently ill-defined by academics and policy-makers alike. As a result, the epistemological and ontological underpinnings of approaches to transparency in IR often sit in tension with their wider theoretical commitments. This article will examine the three primary understandings of transparency used in IR in order to unpack these commitments. It finds that while transparency is often explicitly conceptualized as a property of information, particularly within rationalist scholarship, this understanding rests upon an unarticulated set of sociological assumptions. This analysis suggests that conceptualizing ‘transparency-as-information’ without a wider sociology of knowledge production is highly problematic, potentially obscuring our ability to recognize transparent practices in global governance. Understanding transparency as dialogue, as a social practice rooted in shared cognitive capacities and epistemic frameworks, provides a firmer analytical ground from which to examine transparency in International Relations

Constitutive Expression of Insulin Receptor Substrate (IRS)-1 Inhibits Myogenic Differentiation through Nuclear Exclusion of Foxo1 in L6 Myoblasts

Insulin-like growth factors (IGFs) are well known to play essential roles in enhancement of myogenic differentiation. In this report we showed that initial IGF-I signal activation but long-term IGF-1 signal termination are required for myogenic differentiation. L6 myoblast stably transfected with myc-epitope tagged insulin receptor substrate-1, myc-IRS-1 (L6-mIRS1) was unable to differentiate into myotubes, indicating that IRS-1 constitutive expression inhibited myogenesis. To elucidate the molecular mechanisms underlying myogenic inhibition, IGF-I signaling was examined. IGF-I treatment of control L6 cells for 18 h resulted in a marked suppression of IGF-I stimulated IRS-1 association with the p85 PI 3-kinase and suppression of activation of Akt that correlated with a down regulation of IRS-1 protein. L6-mIRS1 cells, in contrast, had sustained high levels of IRS-1 protein following 18 h of IGF-I treatment with persistent p85 PI 3-kinase association with IRS-1, Akt phosphorylation and phosphorylation of the downstream Akt substrate, Foxo1. Consistent with Foxo1 phosphorylation, Foxo1 protein was excluded from the nuclei in L6-mIRS1 cells, whereas Foxo1 was localized in the nuclei in control L6 cells during induction of differentiation. In addition, L6 cells stably expressing a dominant-interfering form of Foxo1, Δ256Foxo1 (L6-Δ256Foxo1) were unable to differentiate into myotubes. Together, these data demonstrate that IGF-I regulation of Foxo1 nuclear localization is essential for the myogenic program in L6 cells but that persistent activation of IGF-1 signaling pathways results in a negative feedback to prevent myogenesis

Comedian Hosts and the Demotic Turn

Podcasting is a showcase for what cultural studies scholar Graeme Turner coined “the demotic turn” or the increasing visibility of the ordinary person in the today’s media landscape. Collins argues that the emergence of a particular breed of podcasts – comedian-hosted interviews with celebrities – function in an “off-label” manner as a form of self-help or vicarious therapy. The emergence and rapid growth of this genre can attributed to three main factors: a confessional culture, the triumph of experience over expertise, and the democratization allowed by the form’s technology. She explores the link between emotional intimacy and comedy, and analyzes podcasts like Marc Maron’s WTF that are, in expression, a rejection of the pedestal version of stardom

Hypertrophy of mature xenopus muscle fibres in culture induced by synergy of albumin and insulin

The aim of this study was to investigate effects of albumin and insulin separately as well as in combination on mature muscle fibres during long-term culture. Single muscle fibres were dissected from m. iliofibularis of Xenopus laevis and attached to a force transducer in a culture chamber. Fibres were cultured in a serum-free medium at slack length (mean sarcomere length 2.3 μm) for 8 to 22 days. The medium was supplemented with (final concentrations): (1) bovine insulin (6 nmol/L or 200-600 nmol/L), (2) 0.2% bovine albumin or (3) 0.2% bovine albumin in combination with insulin (120 nmol/L). In culture medium with insulin, 50% of the muscle fibres became in-excitable within 7-12 days, whereas the other 50% were stable. Caffeine contractures of in-excitable muscle fibres produced 80.4±2.4% of initial peak tetanic force, indicating impaired excitation-contraction (E-C) coupling in in-excitable fibres. In the presence of albumin, all cultured muscle fibres were stable for at least 10 days. Muscle fibres cultured in medium with insulin or albumin exclusively did not hypertrophy or change the number of sarcomeres in series. In contrast, muscle fibres cultured with both albumin and insulin showed an increase in tetanic force and fibre cross-sectional area of 19.6±2.8% and 32.5±4.9%, respectively, (means±SEM.; P=0.007) after 16.3±1.7 days, whereas the number of sarcomeres in series remained unchanged. We conclude that albumin prevents muscle fibre damage and preserves E-C coupling in culture. Furthermore, albumin is important in regulating muscle fibre adaptation by a synergistic action with growth factors like insulin. © 2008 The Author(s)

C1-Ten Is a Protein Tyrosine Phosphatase of Insulin Receptor Substrate 1 (IRS-1), Regulating IRS-1 Stability and Muscle Atrophy

Muscle atrophy occurs under various catabolic conditions, including insulin deficiency, insulin resistance, or increased levels of glucocorticoids. This results from reduced levels of insulin receptor substrate 1 (IRS-1), leading to decreased phosphatidylinositol 3-kinase activity and thereby activation of FoxO transcription factors. However, the precise mechanism of reduced IRS-1 under a catabolic condition is unknown. Here, we report that C1-Ten is a novel protein tyrosine phosphatase (PTPase) of IRS-1 that acts as a mediator to reduce IRS-1 under a catabolic condition, resulting in muscle atrophy. C1-Ten preferentially dephosphorylated Y612 of IRS-1, which accelerated IRS-1 degradation. These findings suggest a novel type of IRS-1 degradation mechanism which is dependent on C1-Ten and extends our understanding of the molecular mechanism of muscle atrophy under catabolic conditions. C1-Ten expression is increased by catabolic glucocorticoid and decreased by anabolic insulin. Reflecting these hormonal regulations, the muscle C1-Ten is upregulated in atrophy but downregulated in hypertrophy. This reveals a previously unidentified role of C1-Ten as a relevant PTPase contributing to skeletal muscle atrophy.open2

The Contested Politics of Corporate Governance: The Case of the Global Reporting Initiative

The Global Reporting Initiative (GRI) has successfully become institutionalized as the preeminent global framework for voluntary corporate environmental and social reporting. Its success can be attributed to the “institutional entrepreneurs” who analyzed the reporting field and deployed discursive, material, and organizational strategies to change it. GRI has, however, fallen short of the aspirations of its founders to use disclosure to empower nongovernmental organizations (NGOs). The authors argue that its trajectory reflects the power relations between members of the field, their strategic choices and compromises, their ability to mobilize alliances and resources, and constraints imposed by the broader institutions of financial and capital markets. The authors draw three notable implications from this study. First, institutional theory needs to pay more attention to economic structures, strategies, and resources. Second, institutional entrepreneurship by relatively weak societal groups such as NGOs is inherently constrained by the structural power of wider institutions and by the compromises required to initiate change. Third, the strategies of NGOs represent a form of power capable of shifting, if not transforming, the field of corporate governance