Biology subjects

Hung, M.

Publications and source records attributed to Hung, M..

3 recordsLinked to original sources

bioRxiv2024

The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a slowly progressive, multisystemic disorder caused by a CTG repeat expansion in the DMPK 3UTR that leads to global dysregulation of alternative splicing. Here, we employed a composite RNA splicing biomarker called the Myotonic Dystrophy Splice Index (SI), which incorporates 22 disease-specific splice events that sensitively and robustly assesses transcriptomic dysregulation across the disease spectrum. Targeted RNA sequencing was used to derive the SI in 95 muscle biopsies of the tibialis anterior collected from DM1 individuals with baseline (n = 52) and 3-months (n = 37) outcomes. The SI had significant associations with timepoint matched measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk speed (Pearson r = -0.719 and -0.680, respectively). Linear regression modeling showed that the combination of baseline ADF and SI was predictive of strength at 3-months (adjusted R2 = 0.830) in our cohort. These results indicate the SI can reliably capture the association of disease-specific RNA mis-splicing to physical strength and mobility and may be predictive of future function.

molecular biology↗

bioRxiv2023

Cadherin-dependent adhesion is required for muscle stem cell niche anchorage and maintenance

Adhesion between stem cells and their niche provides stable anchorage and signaling cues to sustain properties such as quiescence. Skeletal muscle stem cells (MuSCs) directly adhere to an adjacent myofiber via cadherin-catenin complexes. Previous studies on N- and M-cadherin function in MuSCs revealed that while N-cadherin is required for quiescence, they are collectively dispensable for MuSC niche localization and regenerative activity. While additional cadherins are expressed at low levels, these findings raise the possibility that cadherins are unnecessary for MuSC anchorage to the niche. To address this question, we conditionally removed from MuSCs {beta}- and {gamma}-catenin and, separately, E- and T-catenin, factors essential for cadherin-dependent adhesion. Catenin-deficient MuSCs break quiescence similarly to N-/M-cadherin-deficient MuSCs, but exit the niche, and are depleted. A combination of in vivo, ex vivo, and single cell RNA sequencing approaches reveal that MuSC attrition occurs via a single fate: precocious differentiation, reentry to the niche, and fusion to myofibers. These findings indicate that cadherin-catenin-dependent adhesion is required for anchorage of MuSCs to their niche and preservation of the stem cell compartment. Furthermore, separable, cadherin-regulated functions govern niche localization, quiescence, and stem cell maintenance in MuSCs. SUMMARY STATEMENTGenetic ablation of cadherin-based adhesion in skeletal muscle stem cells triggers activation, niche exit, precocious differentiation, and subsequent depletion of the stem cell pool.

cell biology↗

bioRxiv2018

Lipid interactions enhance activation and potentiation of cystic fibrosis transmembrane conductance regulator (CFTR)

The recent cryo-electron microscopy structures of phosphorylated, ATP-bound CFTR in detergent micelles failed to reveal an open anion conduction pathway as expected on the basis of previous functional studies in biological membranes. We tested the hypothesis that interaction of CFTR with lipids is important for opening of its channel. Interestingly, molecular dynamics studies revealed that phospholipids associate with regions of CFTR proposed to contribute to its channel activity. More directly, we found that CFTR purified together with associated lipids using the amphipol: A8-35, exhibited higher rates of catalytic activity, channel activation and potentiation using ivacaftor, than did CFTR purified in detergent. Catalytic activity in CFTR detergent micelles was partially rescued by addition of phospholipids plus cholesterol, arguing that these lipids contribute directly to its modulation. In summary, these studies highlight the importance of lipids in regulated CFTR channel activation and potentiation.

biophysics↗