bims-musmir 2024-08-25 papers

Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2406787121

Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory.

Christopher M Madl, Yu Xin Wang, Colin A Holbrook, Shiqi Su, Xuechen Shi, Fitzroy J Byfield, Gwendoline Wicki, Iris A Flaig, Helen M Blau.

Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics.

Keywords: dynamic hydrogels; fibrosis; mechanical memory; mechanotransduction; muscle stem cells

DOI: https://doi.org/10.1073/pnas.2406787121

J Clin Neuromuscul Dis. 2024 Sep 01. 26(1): 42-46

Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.

Nicholas Purcell, Georgios Manousakis.

ABSTRACT: Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.

DOI: https://doi.org/10.1097/CND.0000000000000501

Front Immunol. 2024 ;15 1397629

Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

Moemen Eltobgy, Finny Johns, Daniela Farkas, Laura Leuenberger, Sarah P Cohen, Kevin Ho, Sarah Karow, Gabrielle Swoope, Sonal Pannu, Jeffrey C Horowitz, Rama K Mallampalli, Joshua A Englert, Joseph S Bednash.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS.
Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing.
Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport.
Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Keywords: ARDS (acute respiratory disease syndrome); COVID - 19; RNA seq analysis; SARS-CoV-2; longitudinal analysis

DOI: https://doi.org/10.3389/fimmu.2024.1397629

BMC Neurosci. 2024 Aug 22. 25(1): 37

Role of the sympathetic nervous system in cancer-associated cachexia and tumor progression in tumor-bearing BALB/c mice.

Isaias Gutierrez-Leal, Diana Caballero-Hernández, Alonso A Orozco-Flores, Ricardo Gomez-Flores, Deyanira Quistián-Martínez, Patricia Tamez-Guerra, Reyes Tamez-Guerra, Cristina Rodríguez-Padilla.

BACKGROUND: Adipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting.
METHODS: We sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression.
RESULTS: Tumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group.
CONCLUSION: The SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.

Keywords: Adrenergic system; Cancer cachexia; Inflammation; Lymphoma; Sympathectomy; Sympathetic nervous system

DOI: https://doi.org/10.1186/s12868-024-00887-8

Redox Biol. 2024 Aug 19. pii: S2213-2317(24)00288-X. [Epub ahead of print]76 103310

Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals.

Larissa E Vlaming-van Eijk, Marian L C Bulthuis, Bernardina T F van der Gun, Karin I Wold, Alida C M Veloo, María F Vincenti González, Martin H de Borst, Wilfred F A den Dunnen, Jan-Luuk Hillebrands, Harry van Goor, Adriana Tami, Arno R Bourgonje.

BACKGROUND: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R-SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R-SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19.
METHODS: Baseline serum R-SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R-SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS.
RESULTS: Baseline albumin-adjusted serum R-SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R-SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = -9.48, p = 0.023).
CONCLUSION: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R-SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.

Keywords: COVID-19; Coronavirus disease 2019; Long COVID-19; Oxidative stress; Post-COVID-19 syndrome; Redox

DOI: https://doi.org/10.1016/j.redox.2024.103310