Biology subjects

Ortenblad, N.

Publications and source records attributed to Ortenblad, N..

10 recordsLinked to original sources

bioRxiv2025

Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Background Muscle wasting, systemic inflammation, and functional decline are highly prevalent and detrimental in patients with advanced-stage non small cell lung cancer (NSCLC). Methods: In this cross sectional study, we investigated NSCLC associated muscle remodeling by analyzing skeletal muscle biopsies from patients with NSCLC (n = 18) and matched controls (n = 18) using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high resolution respirometry. Findings: NSCLC muscle was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix (ECM), together with remodeling of the inflammatory, immune, ECM and mitochondrial proteome. Additionally, mitochondrial respiratory capacity and morphology were altered in patients with NSCLC, which was associated with increased oxidative stress and dysregulated calcium handling. Concomitantly, we detected STAT3 activation and immune cell alterations, which may negatively impact skeletal muscle health in patients with NSCLC. Finally, we identified a shift in fibro-adipogenic progenitors (FAPs), favoring the CD90 subtype. Mechanistically, conditioned media from patient-derived FAPs reduced myotube width in vitro, uncovering a novel mechanism by which altered paracrine signaling from the muscle resident stromal compartment drives atrophy in cancer cachexia. Interpretation: These findings provide human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape accompany muscle wasting in NSCLC, which may inform therapeutic strategies to preserve skeletal muscle health in patients with cancer.

molecular biology↗

bioRxiv2025

Mitochondrial cristae density is increased following high-intensity interval training in patients with type 2 diabetes

Aims/hypothesisMitochondrial cristae architecture is a key determinant of oxidative capacity in skeletal muscle. While mitochondrial dysfunction is common in type 2 diabetes, it remains unclear whether cristae density is reduced and whether it can be improved by exercise training. We therefore investigated the mitochondrial cristae density in skeletal muscle of patients with type 2 diabetes compared with glucose-tolerant individuals with obesity and lean individuals, and examined the effect of high-intensity interval training (HIIT). MethodsIn a non-randomized intervention study, the effect of an 8-week supervised HIIT intervention combining rowing and cycling was examined in male participants (aged 40-65 years) with type 2 diabetes (n=15), glucose-tolerant individuals with obesity (n=15), and lean individuals (n=18). Muscle biopsies from the m. vastus lateralis were analyzed using transmission electron microscopy (TEM) to quantify mitochondrial cristae density (cristae surface area per mitochondrial volume) and to derive cristae surface area per muscle volume, integrating mitochondrial abundance and ultrastructure. To ensure high stereological precision, a minimum of 49 mitochondrial profiles per sample were analyzed. ResultsNo differences in mitochondrial cristae density were observed between groups at baseline. HIIT induced an [~]7% increase in cristae density across all groups, with the most pronounced adaptations in type 2 fibers and in the intermyofibrillar compartment. At baseline, patients with type 2 diabetes exhibited lower cristae surface area per muscle volume compared with lean individuals. Notably, cristae surface area per muscle volume increased more than mitochondrial volume density alone, reflecting combined structural and volumetric remodeling. Conclusions/interpretationSkeletal muscle mitochondrial cristae density is not different between patients with type 2 diabetes and glucose-tolerant individuals with obesity and lean individuals, and the capacity for cristae remodeling in response to exercise is not affected by type 2 diabetes. These findings highlight the plasticity of mitochondrial architecture and support HIIT as a potent stimulus for improving muscle oxidative and metabolic health, also in type 2 diabetes. Research in Context What is already known about this subject?O_LISkeletal muscle mitochondrial cristae architecture is critical for oxidative phosphorylation and metabolic health. C_LIO_LIType 2 diabetes is associated with altered mitochondrial structure, but whether cristae density is reduced remains unclear. C_LIO_LIPrevious short-term exercise interventions have shown limited or inconsistent effects on mitochondrial cristae density, possibly due to methodological constraints. C_LI What is the key question?O_LICan high-intensity interval training (HIIT) remodel skeletal muscle mitochondrial cristae in patients with type 2 diabetes, and is baseline cristae density altered in this condition? C_LI What are the new findings?O_LIBaseline mitochondrial cristae density does not differ between patients with type 2 diabetes and glucose-tolerant individuals with obesity and lean individuals, but cristae surface area per muscle volume is lower in type 2 diabetes. C_LIO_LIEight weeks of HIIT increased mitochondrial cristae density by [~]7% across all groups, with cristae surface area per muscle volume increasing more than mitochondrial volume density alone. C_LIO_LIExercise-induced cristae remodeling occurs in both muscle fiber types and subcellular compartments, demonstrating preserved structural plasticity in type 2 diabetes. C_LI How might this impact on clinical practice in the foreseeable future?O_LIHIIT represents a potent intervention to improve mitochondrial architecture and potentially enhance muscle oxidative capacity and metabolic health in individuals with type 2 diabetes. C_LI

cell biology↗

bioRxiv2025

Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes

Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria and LDs in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in the shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape compared to small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within the group of athletes, large intermyofibrillar LD profiles correlated with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibres rich in mitochondria.

physiology↗

bioRxiv2024

Effect of high-altitude exposure on skeletal muscle mitochondrial subcellular distribution, ultrastructure and respiration in sea-level residents

Endurance exercise performance is associated with a well-developed skeletal muscle mitochondrial network, which is composed of subsarcolemmal mitochondria interconnected with intermyofibrillar mitochondria bending around the myofibrils. High-altitude exposure is typically incorporated in elite sport training regimens, but little is known about how this network adapts to an environment characterised by tissue hypoxia. For this reason, we investigated how high-altitude exposure affects mitochondrial subcellular distribution, ultrastructure, respiratory control, and intrinsic mitochondrial respiratory capacity. Nine healthy and recreationally active sea-level residents (eight males and one female) resided at an altitude of 3454 m with biopsies collected from the vastus lateralis muscle before and after 7 and 28 days at high altitude. The muscular mitochondrial volume density (MitoVD) increased after high-altitude exposure, driven by an increase in the intermyofibrillar MitoVD. This was however accompanied by a decreased cristae surface area per skeletal muscle fibre volume (MuscularCD) because of a decline in the cristae surface area per mitochondrial volume (MitoCD). Despite a reduced MuscularCD, mass-specific maximal coupled respiration (OXPHOS_CII+CI+ETF) increased slightly, and was considerably elevated when normalised to MuscularCD, suggesting intrinsic adaptations to high altitude. The difference between cristae-specific OXPHOS_CII+CI+ETF and an associated cristae-specific leak respiration (Leak_CII+CI+ETF) indicated a markedly higher degree of coupling between the electron flow in the electron transport system and ATP production. As the effect size 95% confidence intervals includes trivial effects the results need to be substantiated. In conclusion, high-altitude exposure altered mitochondrial subcellular distribution, ultrastructure and induced intrinsic respiratory adaptations.

physiology↗

bioRxiv2023

The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

Summary and graphical abstractDecline in mitochondrial function associates with decreased muscle mass and strength in multiple conditions, including sarcopenia and type 2 diabetes. Optimal treatment could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues controlling muscle mitochondrial plasticity. Here we uncover the mitochondrial-mRNA-stabilizing protein SLIRP, in complex with LRPPRC, as a PGC-1 target that regulates mitochondrial structure, respiration, and mitochondrially-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracted mitochondrial defects induced by loss of LRPPRC/SLIRP, despite sustained low mitochondrially-encoded-mRNA pools, via increased mitoribosome translation capacity. In humans, exercise training robustly increased muscle SLIRP and LRPPRC protein content across exercise modalities and sexes, yet this increase was less prominent in subjects with type 2 diabetes. Our work identifies a mechanism of post-transcriptional mitochondrial regulation in skeletal muscle through mitochondrial mRNA stabilization. It emphasizes exercise as an effective approach to alleviate mitochondrial defects by possibly increasing mitoribosome capacity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/564600v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1cdc6c5org.highwire.dtl.DTLVardef@b4cb1borg.highwire.dtl.DTLVardef@182871corg.highwire.dtl.DTLVardef@7462ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Differential utilisation of subcellular skeletal muscle glycogen pools: A comparative analysis between 1 and 15 minutes of maximal exercise

Distinct subcellular pools of glycogen particles exist within skeletal muscle fibres, distributed both within and between myofibrils and can be found in proximity to, or at a distance from mitochondria. Their precise localisation may influence their degradation rate and role in muscle function. Here, we investigated how exercise at different intensities (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and relative contribution from anaerobic metabolism affects the utilisation of the distinct pools. Further, we investigated how lowered carbohydrate and energy intake affected glycogen volume densities and the storage of glycogen particles (i.e., localisation, size, and number) and their subsequent utilisation during the exercises. Using a randomized, counterbalanced, cross-over design, participants performed two maximal cycle tests of either 1 (n=10) or 15 min (n=10), conducted following consumption of two distinct diets with either high or lowered carbohydrate and energy contents. Muscle biopsies from m. vastus lateralis were obtained before and after the exercises. Intermyofibrillar glycogen was preferentially utilised during the 1-min exercise, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min exercise. The lowered carbohydrate and energy intake decreased the particle size across all subcellular pools and reduced the numerical density in the intramyofibrillar and subsarcolemmal pools, with no effects on the glycogen utilisation during the subsequent exercise. In conclusion, the distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal exercise. Additionally, lowered carbohydrate and energy consumption reduces particle size and numerical density, depending on subcellular localisation.

physiology↗

bioRxiv2023

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre-type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein responses (UPRmt). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes.

physiology↗

bioRxiv2021

Specific ATPases drive compartmentalized glycogen utilization in rat skeletal muscle

Glycogen is a key energy substrate in excitable tissue and especially in skeletal muscle fibers it contributes with a substantial, but also local energy production. A heterogenic subcellular distribution of three distinct glycogen pools in skeletal muscle is proved by transmission electron microscopy (TEM), which is thought to represent the requirements for local energy stores at the subcellular level. Here, we show that the three main energy-consuming ATPases in skeletal muscles (Ca2+-, Na+,K+-, and myosin ATPases) utilize different local pools of glycogen. These results clearly demonstrate compartmentalized glycogen metabolism and emphasize that spatially distinct pools of glycogen particles act as energy substrate for separated energy requiring processes, suggesting a new paradigm for understanding glycogen metabolism in working muscles, muscle fatigue and metabolic disorders.

physiology↗

bioRxiv2020

Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor -like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.

physiology↗

bioRxiv2017

Fundamental Constraints In Synchronous Muscle Limit Superfast Motor Control In Vertebrates

Superfast muscles (SFM) are extremely fast synchronous muscles capable of contraction rates up to 250 Hz, enabling precise motor execution at the millisecond time scale. To allow such speed, the archetypal SFM, found in the toadfish swimbladder, has hallmark structural and kinetic adaptations at each step of the conserved excitation-contraction coupling (ECC) pathway. More recently SFM phenotypes have been discovered in most major vertebrate lineages, but it remains unknown whether all SFM share ECC adaptations for speed, and if SFM arose once, or from independent evolutionary events. Here we use genomic analysis to identify the myosin heavy chain genes expressed in bat and songbird SFM to achieve rapid actomyosin crossbridge kinetics and demonstrate that these are evolutionarily and ontologically distinct. Furthermore, by quantifying cellular morphometry and calcium signal transduction combined with force measurements we show that all known SFM share multiple functional adaptations that minimize ECC transduction times. Our results suggest that SFM evolved independently in sound producing organs in ray-finned fish, birds, and mammals, and that SFM phenotypes operate at a maximum operational speed set by fundamental constraints in synchronous muscle. Consequentially, these constraints set a fundamental limit to the maximum speed of fine motor control.

physiology↗