Biology subjects

Hostrup, M.

Publications and source records attributed to Hostrup, M..

8 recordsLinked to original sources

bioRxiv2025

Deconvoluting fiber type proportions from human skeletal muscle transcriptomics and proteomics data using FibeRtypeR

Muscle fibers are the dominant, multinucleated cell type in skeletal muscle. In humans, they can be classified as slow (type 1) and fast (type 2) fibers, traditionally based on distinct properties of their contractile machinery. Slow and fast fibers are characterized by shared and specific cellular complexities that are pivotal for their adaptive capacity to exercise or role in metabolic disease progression. In this era of omics research, there is a critical need to accurately infer muscle fiber type proportions from bulk tissue omics datasets, as single-fiber approaches are not feasible in large-scale or retrospective studies. Here we present FibeRtypeR, an easy-to-use web application to accurately estimate fiber type proportions from bulk transcriptomics and proteomics datasets: https://muscleapps.ugent.be. FibeRtypeR exploits transcriptomics and proteomics profiles of 1000 fiber-typed individual human skeletal muscle fibers as a reference dataset and is validated against paired immunohistochemical fiber type determinations in 160 muscle biopsies. We show that FibeRtypeR can be applied to public datasets, illustrating the application potential across a wide range of biological contexts such as aging, disease and exercise training. This new freely accessible computational tool will prove valuable to the skeletal muscle research community. Key pointsO_LIBulk muscle omics datasets lack fiber type specific information C_LIO_LIOur new tool, FibeRtypeR, leverages in-house collected single-fiber profiles allowing for accurate fiber type inference C_LIO_LIFibeRtypeR is methodologically robust across omics technologies and workflows C_LIO_LIWe host FibeRtypeR as an intuitive open-access Shiny app, applicable to new and publicly available transcriptomics and proteomics datasets C_LI

physiology↗

bioRxiv2024

Muscle fiber proteomics reveals sex- and fiber type-specific adaptations to resistance training

Skeletal muscle hypertrophy is a hallmark of resistance training that positively impacts health and longevity. However, despite physiological differences between sexes and fiber types, the underlying proteome changes with resistance training have not been studied in a sex- and fiber type-specific manner. Herein, we show sex differences in the fiber type-specific proteome, predominantly in type II fibers. Following 8 weeks of resistance training, substantial remodeling of the human skeletal muscle proteome occurred in a sex- and fiber type-specific manner. Notably, type II fibers exhibited much greater adaptations across both sexes, whereas the main sex-difference was a greater remodeling of intermediate filaments in females. In addition, baseline abundance of proteins involved in translation was highly correlated with fiber hypertrophy, and differed between sexes and fiber types. Thus, translational capacity may partially explain differences in resistance training-induced hypertrophy. Our findings demonstrate key aspects of sex- and fiber type differences in muscle physiology and their contributions to resistance training-induced adaptions.

physiology↗

bioRxiv2023

Insulin and Exercise-induced Phosphoproteomics of Human Skeletal Muscle Identify REPS1 as a New Regulator of Muscle Glucose Uptake

Skeletal muscle regulates glucose uptake in response to insulin and exercise which is critical for maintaining metabolic health. We conducted a comprehensive phosphoproteomic analysis of skeletal muscle from healthy people in response to an acute bout of exercise or insulin stimulation by a hyperinsulinemic euglycemic clamp. Our analysis revealed 233 phosphosites regulated by both exercise and insulin of which most phosphosites were regulated in opposite directions. However, 71 phosphosites on 55 proteins displayed regulation in the same direction, indicating a potential convergence of signaling pathways. We identified the vesicle-associated protein, REPS1, to be phosphorylated at Ser709 in response to both insulin and exercise. REPS1 protein level and Ser709 phosphorylation were closely related to insulin-stimulated glucose uptake in skeletal muscle and required for maximal insulin-stimulated glucose uptake. Furthermore, we observed that insulin triggered phosphorylation of REPS1 Ser709 via P90S6 kinase (RSK) and is impaired in mice and humans with insulin resistance. Collectively, REPS1 is a convergence point for insulin and exercise signaling and a promising therapeutic target in insulin resistance.

biochemistry↗

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

Beyond Myosin Heavy Chains: Ribosomal Specialization Drives Human Skeletal Muscle Fiber Heterogeneity

Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one "slow" (type 1) and two "fast" (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, heterogeneity between and within traditional fiber types remains underexplored. Indeed, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from human vastus lateralis, respectively, we show that MYHs are not the only principal drivers of skeletal muscle fiber heterogeneity. Instead, metabolic, ribosomal, and cell junction proteins are a source of multi-dimensional variation between skeletal muscle fibers. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data suggests that type 2X fibers are not phenotypically distinct to other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy, with fibers shifting towards a non-oxidative phenotype independently of MYH-based fiber type. We also characterize novel transcriptomic and proteomic features of slow and fast skeletal muscle fibers, including identifying several muscle fiber type-specific polypeptides, termed microproteins, encoded by transcripts annotated as non-coding RNA. Overall, our data indicates that skeletal muscle fiber heterogeneity is multi-dimensional with sources of variation beyond myosin heavy chain isoforms.

physiology↗

bioRxiv2023

Reducing the mitochondrial oxidative burden alleviates lipid-induced insulin resistance in human skeletal muscle

Pre-clinical models suggest a causative nexus between mitochondrial oxidative stress and insulin resistance. However, the translational and pathophysiological significance of this mechanism in humans remains unclear. Herein, we employed an invasive in vivo mechanistic approach in humans to manipulate mitochondrial redox state while assessing insulin action. To this end, we combined intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO) in conjunction with insulin clamp studies. During lipid overload, insulin-stimulated muscle glucose uptake, as determined by the femoral arteriovenous balance technique, was increased by mtAO. At the muscle molecular level, mtAO did not affect canonical insulin signaling but augmented insulin-stimulated GLUT4 translocation while decreasing the mitochondrial oxidative burden under lipid oversupply. Ex vivo studies revealed that mtAO ameliorated features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission, in muscle fibers exposed to high intracellular lipid levels. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/535538v2_ufig1.gif" ALT="Figure 1"> View larger version (86K): org.highwire.dtl.DTLVardef@157d44eorg.highwire.dtl.DTLVardef@13358dborg.highwire.dtl.DTLVardef@e958eorg.highwire.dtl.DTLVardef@17cbc6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Beta2-adrenoceptor agonist salbutamol increases leg glucose uptake and metabolic rate but not muscle glycogen resynthesis in recovery from resistance exercise of the quadriceps in lean young men

ContentBeta2-agonists evoke potent acute increases in peripheral glucose uptake and energy expenditure at rest. Exercise has been shown to blunt these effects. Whether this attenuation is extended into recovery from exercise is unknown. ObjectiveTo examine the effect of beta2-agonists on leg glucose uptake and leg metabolic rate in recovery from exercise. DesignIn a randomized, placebo-controlled, cross-over study using arteriovenous balance technique and analysis of thigh muscle biopsies we investigated the effect of 24mg oral salbutamol (a selective beta2-agonist) on leg glucose, oxygen, and lactate at rest, during exercise, and in recovery, as well as on muscle glycogen resynthesis. ParticipantsHealthy, lean, young men (n=12). ResultsLeg glucose uptake tended to be two-fold higher at rest (0.22{+/-}0.12mmol/min, P=0.06). Accumulated leg glucose uptake was higher in recovery (21.1{+/-}6mmol, P=0.018) with salbutamol, but not during exercise. Leg oxygen uptake was 80% greater at rest (11{+/-}2.1mmol/min, P<0.01). Accumulated leg oxygen uptake was higher in recovery (1755{+/-}348mL, P<0.01) with salbutamol, but not during exercise. Muscle glycogen was lower with salbutamol 0.5h (109{+/-}25mmol/mg dry-weight, P<0.01) and 5h (101{+/-}19mmol/mg dry-weight, P<0.01) into recovery, suggestive of augmented glycogen utilization during exercise. There was no difference in glycogen resynthesis or glycogen synthase activity in the 5-hour recovery period with salbutamol. ConclusionsThese findings suggest that while resistance exercise confounds the augmentation of leg glucose uptake and metabolic rate induced by beta2-agonist at rest, this suppression is not conserved into recovery from exercise.

physiology↗

bioRxiv2021

High-Intensity Interval Training Remodels the Proteome and Acetylome of Human Skeletal Muscle

Exercise is an effective strategy in the prevention and treatment of metabolic diseases. Alterations in the skeletal muscle proteome, including post-translational modifications, regulate its metabolic adaptations to exercise. Here, we examined the effect of high-intensity interval training (HIIT) on the proteome and acetylome of human skeletal muscle, revealing the response of 3168 proteins and 1263 lysine acetyl-sites on 464 acetylated proteins. We identified global protein adaptations to exercise training involved in metabolism, excitation-contraction coupling, and myofibrillar calcium sensitivity. Furthermore, HIIT increased the acetylation of mitochondrial proteins, particularly those of complex V. We also highlight the regulation of exercise-responsive histone acetyl-sites. These data demonstrate the plasticity of the skeletal muscle proteome and acetylome, providing insight into the regulation of contractile, metabolic and transcriptional processes within skeletal muscle. Herein, we provide a substantial hypothesis-generating resource to stimulate further mechanistic research investigating how exercise improves metabolic health. Impact statementHostrup and colleagues identify global proteomic and acetylomic adaptations to high-intensity interval training, demonstrating adaptations to processes regulating metabolism and contraction.

physiology↗