Biology subjects

Mitchell, C. J.

Publications and source records attributed to Mitchell, C. J..

6 recordsLinked to original sources

bioRxiv2026

Leg blood flow and muscle oxygenation are reduced when exercising with loads >=40% 1RM compared to loads <=30% 1RM due to increases in contraction induced intramuscular pressure

The critical occluding tension (COT) is the load at which contraction-induced increases in intramuscular pressure (IMP) collapse intramuscular vasculature and impair oxygen delivery. For knee extension resistance exercise, the COT occurs at ~30-40% 1RM, yet few studies have measured IMP alongside convective oxygen delivery. This study examined the interaction between IMP, leg blood flow, and muscle oxygenation during resistance exercise. Twelve participants completed knee extension bouts across a range of loads while vastus lateralis IMP, femoral blood flow (Doppler), blood pressure, muscle oxygenation (NIRS), and electromyography (EMG) were recorded. Mean IMP increased alongside relative load (20% 1RM=19.1(9.4) mmHg; 30% 1RM=22.4(10.4) mmHg; 40% 1RM=27.0(8.7) mmHg; 50% 1RM=31.5(11.5) mmHg; 60% 1RM=41.14(13.8) mmHg; p<0.05). Leg blood flow scaled to rest was similar between 20% and 30% 1RM (p=0.13), 40%, 50%, and 60% 1RM (p>0.05), but different between the 20-30% 1RM and 40-60% 1RM groupings (p<0.05) (20% 1RM=2.6(1.4) times rest; 30% 1RM=1.8(0.5) fold of rest; 40% 1RM=1.4(0.6) fold of rest; 50% 1RM=1.1(0.4) fold of rest; 60% 1RM=1.1(0.5) fold of rest). Muscle oxygenation was lower at 40%, 50%, and 60% 1RM compared to 20% and 30% 1RM (p<0.05). Thus, at [≤]30% 1RM exercising blood flow increased well above rest, indicating preserved microvascular perfusion, whereas at [≥]40% 1RM the rise in IMP was sufficient to impair perfusion and limit blood flow increases. Exercise at or above the COT restricts convective oxygen delivery due to contraction-induced increases in IMP.

physiology↗

bioRxiv2026

Matrix Metalloproteinase Response to Acute Resistance Exercise is Altered in Osteoarthritic Adults with Increased Muscle Collagen and PDGFRα+ Mesenchymal Cells

Background: Knee osteoarthritis (OA) is associated with knee extensor weakness, altered myofibre morphology, reduced satellite cell abundance and fibrillar muscle collagen accumulation in the vastus lateralis (VL). Fibrillar muscle collagen accumulation is associated with reduced knee extensor strength. Yet, its underlying mechanisms remain poorly understood. Satellite cells and PDGFR+ mesenchymal cells express collagen as well as proteins involved in collagen degradation and may be involved in muscle collagen accumulation. The present study assessed knee extensor function and myofibre morphology, satellite cells and PDGFR+ mesenchymal cells in adults with and without moderate-to-severe knee OA. It also investigated collagen remodeling by assessing how enzymes involved in collagen degradation (matrix metalloproteinases [MMPs]) respond to acute resistance exercise in the VL. This study aimed to better understand the cellular contributors to muscle collagen accumulation and knee extensor weakness in knee OA. Methods: Volunteers with and without moderate-to-severe knee OA had a resting muscle biopsy, then completed an acute bout of resistance exercise and had a 72-hour post-exercise biopsy. Knee extensor strength was measured on a Biodex dynamometer. In VL samples, MMP gene expression (qPCR), protein area fraction (immunofluorescence) and enzyme activity (zymography) were assessed. PDGFR+ mesenchymal cells, satellite cells, satellite cell-MMP9 colocalization and myofibre morphology were assessed by immunofluorescence. Fibrillar muscle collagen content was quantified by picrosirius red. Results: Participants with moderate-to-severe knee OA had weaker knee extensors (isometric and isokinetic), reduced muscle quality (isometric and isokinetic) and more fibrillar collagen than controls (12.2 {+/-} 4.8%, 8.4 {+/-} 2.9%, p = 0.006). Fibrillar collagen was negatively correlated with isokinetic concentric torque (r = -0.479, p = 0.006). Volunteers with knee OA had more PDGFR+ mesenchymal cells (p < 0.001) and fewer satellite cells than controls (p = 0.006). In both groups, resistance exercise upregulated MMP2 (p < 0.001), MMP9 (p = 0.001) and MMP14 (p < 0.001) gene expression as well as MMP2 (p < 0.001) and MMP9 (p = 0.001) enzyme activity. MMP2 and MMP9 protein area fraction increased in response to resistance exercise in controls, but this response was blunted in the knee OA group (age x time interaction, p = 0.041). Satellite cell-MMP9 colocalization fold change post-exercise was significantly different between groups (p = 0.048). Volunteers with knee OA had smaller myofibres (p < 0.001) and greater myofibre shape irregularity (p = 0.039), but no differences in thigh lean mass, capillary content or fibre-type distribution. Conclusions: Although exercise stimulated transcriptional and MMP activity responses in both groups, the ECM-specific protein response was impaired in knee OA. The findings suggest that dysregulated ECM remodeling facilitated by MMPs and alterations in PDGFR+ mesenchymal and satellite cell abundance may contribute to muscle collagen accumulation and knee extensor weakness in knee OA.

physiology↗

bioRxiv2024

Network-based modelling reveals cell-type enriched patterns of non-coding RNA regulation during human skeletal muscle remodelling

A majority of human genes produce non-protein-coding RNA (ncRNA), and some have roles in development and disease. Neither ncRNA nor human skeletal muscle is ideally studied using short-read sequencing, so we used a customised RNA pipeline and network modelling to study cell-type specific ncRNA responses during muscle growth at scale. We completed five human resistance-training studies (n=144 subjects), identifying 61% who successfully accrued muscle-mass. We produced 288 transcriptome-wide profiles and found 110 ncRNAs linked to muscle growth in vivo, while a transcriptome-driven network model demonstrated interactions via a number of discrete functional pathways and single-cell types. This analysis included established hypertrophy-related ncRNAs, including CYTOR - which was leukocyte-associated (FDR = 4.9 x10-7). Novel hypertrophy-linked ncRNAs included PPP1CB-DT (myofibril assembly genes, FDR = 8.15 x 10-8), and EEF1A1P24 and TMSB4XP8 (vascular remodelling and angiogenesis genes, FDR = 2.77 x 10-5). We also discovered that hypertrophy lncRNA MYREM shows a specific myonuclear expression pattern in vivo. Our multi-layered analyses established that single-cell-associated ncRNA are identifiable from bulk muscle transcriptomic data and that hypertrophy-linked ncRNA genes mediate their association with muscle growth via multiple cell types and a set of interacting pathways. One Sentence SummaryWe used an optimised transcriptomic strategy to identify a set of ncRNA genes regulated during skeletal muscle hypertrophy in one hundred and forty-four people, with network modelling and spatial imaging providing biological context.

bioinformatics↗

bioRxiv2021

Chronic toxicity of three neonicotinoid insecticides and their mixture on two daphniid species: Daphnia magna and Ceriodaphnia dubia

Neonicotinoid insecticides represent nearly a quarter of the global market and are widely used in agriculture but also for lawn, garden care, and pest control. They are highly water-soluble, persistent in soil, and may enter the aquatic compartment via spray drift, runoff, or leaching, and contribute to downstream aquatic toxicity. Although insects appear to be the most sensitive group to neonicotinoids, other groups, such as crustaceans and birds, may also be affected. Furthermore, most studies focus on single-insecticide exposure and very little is known concerning the impact of neonicotinoid mixtures on aquatic invertebrates. The present study was designed to test potential toxicological effects of an environmentally relevant mixture of imidacloprid, clothianidin, and thiamethoxam on populations of Ceriodaphnia dubia and Daphnia magna under controlled conditions. Chronic toxicity tests were conducted in the laboratory, and survival and reproduction were measured for both species under exposure to nominal concentrations of imidacloprid (0.256 {micro}g/L), clothianidin (3.11 {micro}g/L), thiamethoxam (1.49 {micro}g/L), and a mixture of the three compounds at the same concentrations of the individual compounds. The neonicotinoids did not affect the survival of C. dubia and D. magna founders. Reproduction of C. dubia was affected only by the mixture. All three individual insecticides as well as the mixture caused a significant reduction in the reproduction of D. magna. Our results highlight the complexity of pesticide toxicity and show that traditional toxicological approaches such as acute mortality studies, especially tests with single compounds, can underestimate negative impacts that occur in the environment. HighlightsO_LINeonicotinoids are currently the most frequently used insecticides worldwide. C_LIO_LIAn environmentally relevant mixture of three neonicotinoids was evaluated on two daphniid species. C_LIO_LIThe mixture negatively affected the reproduction of C. dubia and Daphnia magna. C_LIO_LITraditional toxicological approaches with single compounds may underestimate the effects occurring in the environment at low concentrations. C_LI

ecology↗

bioRxiv2019

MOTS-c is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis

Healthy aging can be promoted by enhancing metabolic fitness and physical capacity (1, 2). Mitochondria are chief metabolic organelles with strong implications in aging (3-8). In addition to their prominent role in bioenergetics, mitochondria also coordinate broad physiological functions by communicating to other cellular compartments or distal cells using multiple factors (9, 10), including peptides that are encoded within their own independent genome (11, 12). However, it is unknown if aging is actively regulated by factors encoded in the mitochondrial genome. MOTS-c is a mitochondrial-encoded peptide that regulates metabolic homeostasis (13, 14), in part, by translocating to the nucleus to regulate adaptive nuclear gene expression in response to cellular stress (15-17). Here, we report that MOTS-c is an exercise-induced mitochondrial-encoded peptide that significantly enhanced physical performance when administered to young (2 mo.), middle-aged (12 mo.), and old (22 mo.) mice. In humans, we found that endogenous MOTS-c levels significantly increased in response to exercise in skeletal muscle (11.9-fold) and in circulation (1.5-fold). Systemic MOTS-c treatment in mice significantly enhanced the performance on a treadmill of all age groups (~2-fold). MOTS-c regulated (i) nuclear genes, including those related to metabolism and protein homeostasis, (ii) glucose and amino acid metabolism in skeletal muscle, and (iii) myoblast adaptation to metabolic stress. Late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) improved physical capacity and trended towards increasing lifespan. Our data indicate that aging is regulated by genes that are encoded not only in the nuclear genome (18, 19), but also in the mitochondrial genome. Considering that aging is the major risk factor for multiple chronic diseases (20, 21), our study provides new grounds for further investigation into mitochondrial-encoded regulators of healthy lifespan.

cell biology↗

bioRxiv2017

Towards the human cellular microRNAome

microRNAs are short RNAs that serve as master regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell autonomously and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data has caused considerable confusion and comprehensive cell-level data does not yet exist. Here we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues. It identified both specific and ubiquitous patterns of expression that strongly correlate with adjacent super-enhancer activity. Analysis of unaligned RNA reads uncovered 207 unknown minor strand (passenger) microRNAs of known microRNA loci and 2,632 novel putative microRNA loci. Although cancer cell lines generally recapitulated the expression patterns of matched primary cells, their isomiR sequence families exhibited increased disorder suggesting Drosha and Dicer-dependent microRNA processing variability. Cell-specific patterns of microRNA expression were used to deconvolute variable cellular composition of adipose tissue samples highlighting one use of this cell-specific microRNA expression data. Characterization of cellular microRNA expression across a wide variety of cell types provides a new understanding of this critical regulatory RNA species.

genomics↗