Leadership in PhD (LeaP): A longitudinal leadership skill building program for underrepresented biomedical research trainees

Increasing diversity in the biomedical research workforce is a critical national issue. Particularly concerning is the lack of representation at more advanced career stages/in leadership positions. While there are numerous institutional initiatives promoting professional research skills (i.e., grant writing, presenting, networking) for underrepresented (UR) PhD trainees, there are comparatively fewer opportunities for leadership development. We present a blueprint for Leadership in PhD (LeaP), a cohort-based program aiming to equip UR biomedical research trainees with skills to succeed as academic, industry, and community leaders. In contrast to intensive short-term programs or workshops, LeaP is a longitudinal 4-year experience with an blend of didactic, self-directed, and experiential learning. First year trainees receive foundational didactic instruction on core leadership concepts coupled with facilitated peer discussions and one-on-one coaching support. We outline a program evaluation framework that assesses student learning, satisfaction, and program efficacy. Evaluation data from the inaugural year is presented and discussed

Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay.

Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38α/β MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis

Nek4 Status Differentially Alters Sensitivity to Distinct Microtubule Poisons

2011 February 1Microtubule poisons are widely used in cancer treatment, but the factors determining the relative efficacy of different drugs in this class remain obscure. In this study, we identified the NIMA kinase Nek4 in a genetic screen for mediators of the response to Taxol, a chemotherapeutic agent that stabilizes microtubules. After Taxol treatment, Nek4 promoted microtubule outgrowth, whereas Nek4 deficiency impaired G2-M arrest and decreased formation of mitotic-like asters. In contrast, Nek4 deficiency sensitized cells to vincristine, which destabilizes microtubules. Therefore, Nek4 deficiency may either antagonize or agonize the effects of microtubule poisons, depending on how they affect microtubule polymerization. Of note, Nek4 gene maps to a commonly deleted locus in non-small cell lung cancer. Thus, Nek4 deletion in this disease may rationalize the use of particular types of microtubule poisons for lung cancer therapy.Rita Allen Foundation (Fellow)National Institutes of Health (U.S.) (Grant RO1 CA128803-01)Massachusetts Institute of Technology. Dept. of Biology (Training Grant

Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD

Muscle stem cells contribute to long‐term tissue repletion following surgical sepsis

Abstract Background Over the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi‐organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day‐to‐day activities and are directly associated with poor quality of life. Methods Mice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late‐effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post‐necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7‐positive nuclei per myofibre), post‐sepsis whole muscle metabolomics and MuSC isolation and high‐content transcriptional profiling. Results We report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post‐sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post‐sepsis muscle recovery (maintenance of 5–8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post‐sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis‐recovered mice exhibited evidence of impaired muscle regeneration compared with non‐septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post‐sepsis mice and found clear transcriptional differences in all post‐sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001). Conclusions Our data show that MuSCs and muscle regeneration are required for effective post‐sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post‐sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors

Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy

Hereditary muscle diseases are disabling disorders lacking effective treatments. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy (GNEM) is an autosomal recessive distal myopathy with rimmed vacuoles typically manifesting in late adolescence/early adulthood. GNE encodes the rate-limiting enzyme in sialic acid biosynthesis, which is necessary for the proper function of numerous biological processes. Outside of the causative gene, very little is known about the mechanisms contributing to the development of GNE myopathy. In the present study, we aimed to address this knowledge gap by querying the underlying mechanisms of GNE myopathy using a patient-derived induced pluripotent stem-cell (iPSC) model. Control and patient-specific iPSCs were differentiated down a skeletal muscle lineage, whereby patient-derived GNEM iPSC clones were able to recapitulate key characteristics of the human pathology and further demonstrated defects in myogenic progression. Single-cell RNA sequencing time course studies revealed clear differences between control and GNEM iPSC-derived muscle precursor cells (iMPCs), while pathway studies implicated altered stress and autophagy signaling in GNEM iMPCs. Treatment of GNEM patient-derived iMPCs with an autophagy activator improved myogenic differentiation. In summary, we report an in vitro, iPSC-based model of GNE myopathy and implicate defective myogenesis as a contributing mechanism to the etiology of GNE myopathy

Tackling brain and muscle dysfunction in acute respiratory distress syndrome survivors: National Heart, Lung, and Blood Institute Workshop Report

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproven. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and wellbeing of ARDS survivors