Biology subjects

Lavin, K.

Publications and source records attributed to Lavin, K..

4 recordsLinked to original sources

bioRxiv2025

Distinct Myogenic Stages Recapitulate Transcriptomic Networks in COPD Cachexia

BackgroundCachexia is an extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD) characterized by weight loss and muscle wasting. Transcriptomic analysis of skeletal muscle may provide insight to COPD-cachexia-relevant dysregulation, including at the mitochondrial level, where dysfunction is a hallmark of muscle wasting. As muscle biopsies are invasive and yield finite tissue, human muscle derived cultures (HMDCs) can expand limited biopsy material for studying skeletal muscle dysregulation. However, utility of such models depends on their recapitulation of bulk skeletal muscle transcriptomic signatures. To address this, we tested whether COPD and COPD-cachexia dysregulated transcriptional signatures in bulk skeletal muscle are preserved across stages of early differentiation. MethodsVastus lateralis biopsies were collected from 15 (7M/8F, 64{+/-}9 years) participants; COPD n=6, COPD cachexia n=4, and n=5 age-matched controls. Cachexia was defined as weight loss coupled with reduced muscle strength, fatigue, anorexia, low muscle mass and/or systemic inflammation. Satellite cells were isolated and differentiated into HDMCs (myoblasts, myocytes, and myotubes). Transcriptomics data was generated from bulk skeletal muscle and HDMCs. Differential expression analysis identified transcripts significantly dysregulated (p<0.05) in COPD and/or COPD-cachexia. Weighted gene co-expression network analysis (WGCNA) preformed at the whole transcriptome and mitochondrial transcriptome levels, identified modules of co-expressed genes. Modules were tested for correlation with clinical traits and preservation between bulk tissue and HDMCs (Z-summary >2). Gene set enrichment analysis was performed for all modules. Results660 genes were significantly differentially expressed between COPD and control bulk skeletal muscle. The top upregulated and downregulated genes were IL21R-AS1 (Log2-Fold-Change [L2FC]=5.3, p=4.2x10-5) and top downregulated POU5F1B (L2FC=-5.8, p=3.1x10-2), respectively. Among the 492 genes significantly differentially expressed between COPD and COPD-cachexia bulk skeletal muscle. The top upregulated and downregulated genes were LINC02274 (L2FC=5.6, p=3.6x10-5) and ZFY (L2FC=-6.1, p=9.7x10-3) respectively. Modules 1, 9, A, B, D and H correlated with cachexia-relevant traits, and Modules 3, 7, G, and I correlated most strongly with COPD severity. Most modules (1, 2, 4, 7, 8, 9, A, B, H) were preserved across all states; Modules D and G were preserved in myoblasts only, and Module I in myotubes only. Preserved modules were enriched for contractile, inflammatory, oxidative phosphorylation, and fatty acid metabolism pathways. ConclusionsCo-expression modules linked to COPD and COPD-cachexia in bulk skeletal muscle were broadly preserved across all differentiation stages, with myoblast and myotubes most completely recapitulating disease-relevant transcriptional signatures. These findings support HMDCs, as tractable in vitro models preserving contractile, inflammatory, and mitochondrial signatures of COPD-associated muscle dysfunction.

genetics↗

bioRxiv2025

DNA Methylation Dynamics of Dose-dependent Acute Exercise, Training Adaptation, and Detraining

Exercise and diet are direct physical contributors to human health, wellness, resilience, and performance1-5. Endurance and resistance training are known to improve healthspan through various biological processes such as mitochondrial function6-8, telomere maintenance9, and inflammaging10. Although several training prescriptions have been defined with specific merits 1,10-20, the long-term effects of these in terms of their molecular alterations have not yet been well explored. In this study, we focus on two combined endurance and resistance training programs: (1) traditional moderate-intensity continuous endurance and resistance exercise (TRAD) and (2) a variation of high-intensity interval training (HIIT) we refer to as high intensity tactical training (HITT), to assess the dynamics of DNA methylation (DNAm) in blood and muscle derived from males (N=23) and females (N=31), over a 12-week period of training followed by a 4-week period of detraining, sampled at pre-exercise and acute time points, totaling 528 samples. Due to its rapid responsiveness to stimuli and its stability, DNAm has been known to facilitate regulatory cascades that significantly affect various physiological processes and pathways. We find that several thousand differentially methylated regions (DMRs) associated with acute exercise in blood, many of which are shared across males and females. This trend is reversed when comparing the baseline (pre-exercise) time points or post-exercise timepoints at the untrained state with those at the post-conditioned state. Here, muscle shows majority of DNAm changes, with most of those being unique. We also find several hundred "memory" DMRs in muscle that maintain the gain or loss of methylation after four weeks of inactivity. Comparing phenotypic measurements, we find specific DMRs that correlate significantly with mitochondrial function and myofiber switching. Using machine learning, we select a subset of DMRs that are most characteristic of training modalities, sex and timepoint. Most of the DMRs are enriched in pathways associated with immune function, cell differentiation, and exercise adaptation. These findings reveal mechanisms by which exercise- and training-induced epigenetic changes alter immune surveillance, mitochondrial function, and inflammatory response, and underscore the relevance of epigenetic plasticity to health monitoring and wellness.

genomics↗

bioRxiv2024

Serum metabolomics signatures after an acute bout of combined traditional or high-intensity tactical training in young males and females

Exercise is a multipotent stimulus that results in large-scale dynamic changes to the systemic molecular profile. Alternative exercise prescriptions and doses would be expected to result in distinct signatures due to differences in duration and intensity. We tested two novel combined endurance and resistance exercise regimens to better understand how differing prescriptions alter the acute metabolomics response at multiple timepoints up to 24h post-exercise. Serum metabolomics for n=37 untrained individuals was analyzed for participants completing traditional combined exercise [TRAD; n = 20 (11M/9F)] or high-intensity tactical training [HITT; n= 17 (8M/9F)] before exercise (pre), and immediately (h0), 3 and 24 h post-exercise (h3 and h24, respectively). We found minimal metabolites had a group by time interaction (2 with FDR < 0.10; 31 with nominal p < 0.05;), but both stimuli resulted in large-scale within-group changes to the circulating metabolome. TRAD consistently had greater numbers of differentially abundant metabolites (FDR < 0.10) as compared to HITT at h0 (431 vs. 333), h3 (435 vs. 331) and h24 (168 vs. 76). The major metabolite classes altered were related to key energy substrates for both groups at h0 (e.g., glucose, pyruvate) and energy replenishment for h3 and h24 (e.g., 12,13 diHOME, palmitoylcarnitine, free fatty acids). In summary, our data are the first to describe the acute changes in the circulating metabolome following combined endurance and resistance exercise. Additionally, we show the two distinct doses of combined exercise led to generally similar patterns of responses, with the longer duration TRAD dose resulting in a higher magnitude of change.

physiology↗

bioRxiv2022

Assessing the impact of boldine on the gastrocnemius using multiomic profiling at 7 and 28 days post-complete spinal cord injury in young male mice

Spinal cord injury (SCI) results in rapid muscle loss. The mechanisms of muscle atrophy have been well-described but there is limited information specific to SCI. Exogenous molecular interventions to slow muscle atrophy in severe-to-complete SCI have been relatively ineffective and the wide-ranging physiologic response to SCI requires the search for novel therapeutic targets. Connexin hemichannels (CxHC) allow non-selective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (Peumus boldus), has shown promising pre-clinical results in slowing atrophy during sepsis and dysferlinopathy. We administered 50 mg/kg/d of boldine to spinal cord transected mice beginning 3 d post-injury. Tissue was collected 7 and 28 d post-SCI and the gastrocnemius was used for multiomic profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 d post-SCI. SCI resulted in the differential expression of ~7,700 and ~2,000 genes at 7 and 28 d, respectively, compared to sham animals, with enrichment for pathways associated with ribosome biogenesis, translation and oxidative phosphorylation. Boldine altered the expression of ~150 genes at 7 d and ~110 genes at 28 d post-SCI. Methylation analyses highlighted distinct patterns at both 7 and 28 d following SCI both with and without boldine. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it preserved or attenuated SCI-induced changes across the metabolome, transcriptome and methylome.

physiology↗