Publications by authors named "Christoph Handschin"

103 Publications

Exercise-linked improvement in age-associated loss of balance is associated with increased vestibular input to motor neurons.

Aging Cell 2020 12 11;19(12):e13274. Epub 2020 Nov 11.

Biozentrum, University of Basel, Basel, Switzerland.

Age-associated loss of muscle function is exacerbated by a concomitant reduction in balance, leading to gait abnormalities and falls. Even though balance defects can be mitigated by exercise, the underlying neural mechanisms are unknown. We now have investigated components of the proprioceptive and vestibular systems in specific motor neuron pools in sedentary and trained old mice, respectively. We observed a strong age-linked deterioration in both circuits, with a mitigating effect of exercise on vestibular synapse numbers on motor neurons, closely associated with an improvement in gait and balance in old mice. Our results thus describe how the proprioceptive and vestibular systems are modulated by age and exercise, and how these changes affect their input to motor neurons. These findings not only make a strong case for exercise-based interventions in elderly individuals to improve balance, but could also lead to targeted therapeutic interventions aimed at the respective neuronal circuitry.
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http://dx.doi.org/10.1111/acel.13274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744958PMC
December 2020

PGC-1β-expressing POMC neurons mediate the effect of leptin on thermoregulation in the mouse.

Sci Rep 2020 10 15;10(1):16888. Epub 2020 Oct 15.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056, Basel, Switzerland.

The arcuate nucleus (ARC) of the hypothalamus is a key regulator of food intake, brown adipose tissue (BAT) thermogenesis, and locomotor activity. Whole-body deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1β) disrupts mouse circadian locomotor activity and BAT-regulated thermogenesis, in association with altered gene expression at the central level. We examined whether PGC-1β expression in the ARC is required for proper energy balance and locomotor behavior by generating mice lacking the PGC-1β gene specifically in pro-opiomelanocortin (POMC) neurons. POMC neuron-specific deletion of PGC-1β did not impact locomotor behavior, food intake, body composition, energy fuel utilization and metabolic rate in fed, 24-h fasted and 24-h refed conditions. In contrast, in the fed state, deletion of PGC-1β in POMC cells elevated core body temperature during the nighttime period. Importantly, this higher body temperature is not associated with changes in BAT function and gene expression. Conversely, we provide evidence that mice lacking PGC-1β in POMC neurons are more sensitive to the effect of leptin on heat dissipation. Our data indicate that PGC-1β-expressing POMC neurons are part of a circuit controlling body temperature homeostasis and that PGC-1β function in these neurons is involved in the thermoregulatory effect of leptin.
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http://dx.doi.org/10.1038/s41598-020-73794-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567876PMC
October 2020

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia.

Nat Commun 2020 09 9;11(1):4510. Epub 2020 Sep 9.

Biozentrum, University of Basel, Basel, Switzerland.

With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.
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http://dx.doi.org/10.1038/s41467-020-18140-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481251PMC
September 2020

Lifestyle vs. pharmacological interventions for healthy aging.

Aging (Albany NY) 2020 01 10;12(1):5-7. Epub 2020 Jan 10.

Biozentrum, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.18632/aging.102741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977688PMC
January 2020

How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Biozentrum, University of Basel, 4056 Basel, Switzerland.

Epigenetic changes are a hallmark of short- and long-term transcriptional regulation, and hence instrumental in the control of cellular identity and plasticity. Epigenetic mechanisms leading to changes in chromatin structure, accessibility for recruitment of transcriptional complexes, and interaction of enhancers and promoters all contribute to acute and chronic adaptations of cells, tissues and organs to internal and external perturbations. Similarly, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is activated by stimuli that alter the cellular energetic demand, and subsequently controls complex transcriptional networks responsible for cellular plasticity. It thus is of no surprise that PGC-1α is under the control of epigenetic mechanisms, and constitutes a mediator of epigenetic changes in various tissues and contexts. In this review, we summarize the current knowledge of the link between epigenetics and PGC-1α in health and disease.
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http://dx.doi.org/10.3390/ijms20215449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862278PMC
October 2019

PGC-1α plays a pivotal role in simvastatin-induced exercise impairment in mice.

Acta Physiol (Oxf) 2020 04 4;228(4):e13402. Epub 2019 Nov 4.

Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.

Aim: Statins decrease cardiovascular complications, but can induce myopathy. Here, we explored the implication of PGC-1α in statin-associated myotoxicity.

Methods: We treated PGC-1α knockout (KO), PGC-1α overexpression (OE) and wild-type (WT) mice orally with 5 mg simvastatin kg  day for 3 weeks and assessed muscle function and metabolism.

Results: In WT and KO mice, but not in OE mice, simvastatin decreased grip strength, maximal running distance and vertical power assessed by ergometry. Post-exercise plasma lactate concentrations were higher in WT and KO compared to OE mice. In glycolytic gastrocnemius, simvastatin decreased mitochondrial respiration, increased mitochondrial ROS production and free radical leak in WT and KO, but not in OE mice. Simvastatin increased mRNA expression of Sod1 and Sod2 in glycolytic and oxidative gastrocnemius of WT, but decreased it in KO mice. OE mice had a higher mitochondrial DNA content in both gastrocnemius than WT or KO mice and simvastatin exhibited a trend to decrease the citrate synthase activity in white and red gastrocnemius in all treatment groups. Simvastatin showed a trend to decrease the mitochondrial volume fraction in both muscle types of all treatment groups. Mitochondria were smaller in WT and KO compared to OE mice and simvastatin further reduced the mitochondrial size in WT and KO mice, but not in OE mice.

Conclusions: Simvastatin impairs skeletal muscle function, muscle oxidative metabolism and mitochondrial morphology preferentially in WT and KO mice, whereas OE mice appear to be protected, suggesting a role of PGC-1α in preventing simvastatin-associated myotoxicity.
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http://dx.doi.org/10.1111/apha.13402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100017PMC
April 2020

JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms.

Blood 2019 11;134(21):1832-1846

Experimental Hematology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
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http://dx.doi.org/10.1182/blood.2019000162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872961PMC
November 2019

BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle.

Proc Natl Acad Sci U S A 2019 08 18;116(32):16111-16120. Epub 2019 Jul 18.

Biozentrum, University of Basel, CH-4056 Basel, Switzerland;

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.
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http://dx.doi.org/10.1073/pnas.1900544116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690026PMC
August 2019

Peroxisome proliferator-activated receptor γ coactivator 1α regulates mitochondrial calcium homeostasis, sarcoplasmic reticulum stress, and cell death to mitigate skeletal muscle aging.

Aging Cell 2019 10 10;18(5):e12993. Epub 2019 Jul 10.

Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Basel, Switzerland.

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1α overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor α-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1α. As a result, PGC-1α prevents tubular aggregate formation and cell death pathway activation in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1α in muscle cells. Accordingly, mice with muscle-specific gain-of-function and loss-of-function of PGC-1α exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1α on muscle function and overall health span in aging.
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http://dx.doi.org/10.1111/acel.12993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718523PMC
October 2019

Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance.

Nat Commun 2019 06 24;10(1):2767. Epub 2019 Jun 24.

Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, Biomedicum C5, 171 77, Stockholm, Sweden.

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.
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http://dx.doi.org/10.1038/s41467-019-10712-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591322PMC
June 2019

Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics.

Cell Rep 2019 04;27(5):1551-1566.e5

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1α, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).
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http://dx.doi.org/10.1016/j.celrep.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506687PMC
April 2019

Pharmacological targeting of age-related changes in skeletal muscle tissue.

Pharmacol Res 2020 04 4;154:104191. Epub 2019 Mar 4.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056, Basel, Switzerland. Electronic address:

Sarcopenia, the age-related loss of skeletal muscle mass and function, increases the risk of developing chronic diseases in older individuals and is a strong predictor of disability and death. Because of the ongoing demographic transition, age-related muscle weakness is responsible for an alarming and increasing contribution to health care costs in Western countries. Exercise-based interventions are most successful in preventing the decline in skeletal muscle mass and in preserving or ameliorating functional capacities with increasing age. However, other treatment options are still scarce. In this review, we explore currently applied nutritional and pharmacological approaches to mitigate age-related muscle wasting, and discuss potential future therapeutic avenues.
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http://dx.doi.org/10.1016/j.phrs.2019.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100900PMC
April 2020

Endocrine Crosstalk Between Skeletal Muscle and the Brain.

Front Neurol 2018 24;9:698. Epub 2018 Aug 24.

Biozentrum, University of Basel, Basel, Switzerland.

Skeletal muscle is an essential regulator of energy homeostasis and a potent coordinator of exercise-induced adaptations in other organs including the liver, fat or the brain. Skeletal muscle-initiated crosstalk with other tissues is accomplished though the secretion of myokines, protein hormones which can exert autocrine, paracrine and long-distance endocrine effects. In addition, the enhanced release or uptake of metabolites from and into contracting muscle cells, respectively, likewise can act as a powerful mediator of tissue interactions, in particular in regard to the central nervous system. The present review will discuss the current stage of knowledge regarding how exercise and the muscle secretome improve a broad range of brain functions related to vascularization, neuroplasticity, memory, sleep and mood. Even though the molecular and cellular mechanisms underlying the communication between muscle and brain is still poorly understood, physical activity represents one of the most effective strategies to reduce the prevalence and incidence of depression, cognitive, metabolic or degenerative neuronal disorders, and thus warrants further study.
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http://dx.doi.org/10.3389/fneur.2018.00698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117390PMC
August 2018

Muscle Wasting Diseases: Novel Targets and Treatments.

Annu Rev Pharmacol Toxicol 2019 01 27;59:315-339. Epub 2018 Aug 27.

Biozentrum, University of Basel, 4056 Basel, Switzerland; email: ,

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.
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http://dx.doi.org/10.1146/annurev-pharmtox-010818-021041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701981PMC
January 2019

Relation of nNOS isoforms to mitochondrial density and PGC-1alpha expression in striated muscles of mice.

Nitric Oxide 2018 07 17;77:35-43. Epub 2018 Apr 17.

Institute of Physiology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.

The expression of neuronal NO synthase (nNOS) alpha- and beta-isoforms in skeletal muscle is well documented but only little information is available about their regulation/functions. Using different mouse models, we now assessed whether the expression of nNOS-isoforms in muscle fibers is related to mitochondria content/activity and regulated by peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Catalytic histochemistry revealed highest nNOS-concentrations to be present in type-2 oxidative muscle fibers. Differences in mitochondrial density between nNOS-KO-mice and WT-littermates established by morphometry after transmission electron microscopy were significant in the oxidative portion of the tibialis anterior muscle (TA) but not in rectus femoris muscle (RF) indicating an nNOS-dependent mitochondrial pool in TA. Quantitative immunoblotting displayed the nNOS alpha-isoform to preponderate in those striated muscles of C57BL/6-mice that comprise of many type-2 oxidative fibers, e.g. TA, while roughly even levels of the two nNOS-isoforms were expressed in those muscles that mainly consist of type-2 glycolytic fibers, e.g. RF. Differences in citrate synthase-activity in muscle homogenates between nNOS-KO-mice and WT-littermates were positively related to nNOS alpha-isoform levels. In transgenic-mice over-expressing muscular PGC-1alpha compared to WT-littermates, immunoblotting revealed a significant shift in nNOS-expression in favor of the alpha-isoform in six out of eight striated muscles (exceptions: soleus muscle and tongue) without consistent relationship to changes in the expression of mitochondrial markers. In summary, our study demonstrated the nNOS alpha-isoform expression to be related to mitochondrial content/activity and to be up-regulated by up-stream PGC-1alpha in striated muscles, particularly in those enriched with type-2 oxidative fibers implying a functional convergence of the two signaling systems in these fibers.
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http://dx.doi.org/10.1016/j.niox.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697538PMC
July 2018

Moderate Modulation of Cardiac PGC-1α Expression Partially Affects Age-Associated Transcriptional Remodeling of the Heart.

Front Physiol 2018 21;9:242. Epub 2018 Mar 21.

Biozentrum, University of Basel, Basel, Switzerland.

Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1α in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Young mice with reduced cardiac expression of PGC-1α recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1α counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1α in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging.
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http://dx.doi.org/10.3389/fphys.2018.00242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871735PMC
March 2018

Injected Human Muscle Precursor Cells Overexpressing PGC-1 Enhance Functional Muscle Regeneration after Trauma.

Stem Cells Int 2018 21;2018:4658503. Epub 2018 Jan 21.

Department of Urology, Laboratory for Tissue Engineering and Stem Cell Therapy, University Hospital Zürich, University of Zürich, Frauenklinikstrasse 10, 8091 Zürich, Switzerland.

While many groups demonstrated new muscle tissue formation after muscle precursor cell (MPC) injection, the capacity of these cells to heal muscle damage, for example, sphincter in stress urinary incontinence, in long-term is still limited. Therefore, the first goal of our project was to optimize the functional regenerative potential of hMPC by genetic modification to overexpress human peroxisome proliferator-activated receptor gamma coactivator 1-alpha (hPGC-1), key regulator of exercise-mediated adaptation. Moreover, we aimed at establishing a feasible methodology for noninvasive PET visualization of implanted cells and their microenvironment in muscle crush injury model. PGC-1-bioengineered muscles showed enhanced marker expression for myogenesis (-actinin, MyHC, and Desmin), vascularization (VEGF), neuronal (ACHE), and mitochondrial (COXIV) activity. Consistently, use of hPGC-1_hMPCs produced significantly increased contractile force one to three weeks postinjury. PET imaging showed distinct differences in radiotracer signals ([F]Fallypride and [C]Raclopride (both targeting dopamine 2 receptors (D2R)) and [Cu]NODAGA-RGD (targeting neovascularization)) between GFP_hMPCs and hD2R_hPGC-1_hMPCs. After muscle harvesting, inflammation levels were in parallel to radiotracer uptake amount, with significantly lower uptake in hPGC-1 overexpressing samples. In summary, we facilitated early functional muscle tissue regeneration, introducing a novel approach to improve skeletal muscle regeneration. Besides successful tracking of hMPCs in muscle crush injuries, we showed that in high-inflammation areas, the specificity of radioligands might be significantly reduced, addressing a possible bottleneck of neovascularization PET imaging.
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http://dx.doi.org/10.1155/2018/4658503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827889PMC
January 2018

Over-expression of a retinol dehydrogenase (SRP35/DHRS7C) in skeletal muscle activates mTORC2, enhances glucose metabolism and muscle performance.

Sci Rep 2018 01 12;8(1):636. Epub 2018 Jan 12.

Departments of Anesthesia and of Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031, Basel, Switzerland.

SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C dehydrogenase/ reductase family 7. Here we show that its over-expression in mouse skeletal muscles induces enhanced muscle performance in vivo, which is not related to alterations in excitation-contraction coupling but rather linked to enhanced glucose metabolism. Over-expression of SRP-35 causes increased phosphorylation of Akt, triggering plasmalemmal targeting of GLUT4 and higher glucose uptake into muscles. SRP-35 signaling involves RARα and RARγ (non-genomic effect), PI3K and mTORC2. We also demonstrate that all-trans retinoic acid, a downstream product of the enzymatic activity of SRP-35, mimics the effect of SRP-35 in skeletal muscle, inducing a synergistic effect with insulin on AKT phosphorylation. These results indicate that SRP-35 affects skeletal muscle metabolism and may represent an important target for the treatment of metabolic diseases.
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http://dx.doi.org/10.1038/s41598-017-18844-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766524PMC
January 2018

Plasticity of the Muscle Stem Cell Microenvironment.

Adv Exp Med Biol 2017 ;1041:141-169

Biozentrum, University of Basel, Basel, Switzerland.

Satellite cells (SCs) are adult muscle stem cells capable of repairing damaged and creating new muscle tissue throughout life. Their functionality is tightly controlled by a microenvironment composed of a wide variety of factors, such as numerous secreted molecules and different cell types, including blood vessels, oxygen, hormones, motor neurons, immune cells, cytokines, fibroblasts, growth factors, myofibers, myofiber metabolism, the extracellular matrix and tissue stiffness. This complex niche controls SC biology-quiescence, activation, proliferation, differentiation or renewal and return to quiescence. In this review, we attempt to give a brief overview of the most important players in the niche and their mutual interaction with SCs. We address the importance of the niche to SC behavior under physiological and pathological conditions, and finally survey the significance of an artificial niche both for basic and translational research purposes.
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http://dx.doi.org/10.1007/978-3-319-69194-7_8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850985PMC
May 2018

PGC-1α affects aging-related changes in muscle and motor function by modulating specific exercise-mediated changes in old mice.

Aging Cell 2018 02 25;17(1). Epub 2017 Oct 25.

Biozentrum, University of Basel, Basel, Switzerland.

The age-related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age-associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulatory hub in endurance exercise adaptation with decreased expression in old muscle, we studied the involvement of PGC-1α in the therapeutic effect of exercise in aging. Intriguingly, PGC-1α muscle-specific knockout and overexpression, respectively, precipitated and alleviated specific aspects of aging-related deterioration of muscle function in old mice, while other muscle dysfunctions remained unchanged upon PGC-1α modulation. Surprisingly, we discovered that muscle PGC-1α was not only involved in improving muscle endurance and mitochondrial remodeling, but also phenocopied endurance exercise training in advanced age by contributing to maintaining balance and motor coordination in old animals. Our data therefore suggest that the benefits of exercise, even when performed at old age, extend beyond skeletal muscle and are at least in part mediated by PGC-1α.
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http://dx.doi.org/10.1111/acel.12697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770876PMC
February 2018

Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls.

Biochem Pharmacol 2018 01 20;147:211-220. Epub 2017 Oct 20.

Biozentrum, University of Basel, Basel, Switzerland. Electronic address:

Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping. In contrast, dietary supplements with a higher safety margin exert milder outcomes. In recent years, the design of pharmacological agents that activate the training program, so-called "exercise mimetics", has been proposed, although the feasibility of such an approach is highly debated. In this review, the most recent insights into key regulatory factors and therapeutic approaches aimed at leveraging exercise adaptations are discussed.
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http://dx.doi.org/10.1016/j.bcp.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850978PMC
January 2018

Role of Nuclear Receptors in Exercise-Induced Muscle Adaptations.

Cold Spring Harb Perspect Med 2017 Jun 1;7(6). Epub 2017 Jun 1.

Biozentrum, University of Basel, Basel 4056, Switzerland.

Skeletal muscle is not only one of the largest, but also one of the most dynamic organs. For example, plasticity elicited by endurance or resistance exercise entails complex transcriptional programs that are still poorly understood. Various signaling pathways are engaged in the contracting muscle fiber and collectively culminate in the modulation of the activity of numerous transcription factors (TFs) and coregulators. Because exercise confers many benefits for the prevention and treatment of a wide variety of pathologies, pharmacological activation of signaling pathways and TFs is an attractive avenue to elicit therapeutic effects. Members of the nuclear receptor (NR) superfamily are of particular interest owing to the presence of well-defined DNA- and ligand-binding domains. In this review, we summarize the current understanding of the involvement of NRs in muscle biology and exercise adaptation.
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http://dx.doi.org/10.1101/cshperspect.a029835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453380PMC
June 2017

Muscle PGC-1α is required for long-term systemic and local adaptations to a ketogenic diet in mice.

Am J Physiol Endocrinol Metab 2017 05 21;312(5):E437-E446. Epub 2017 Feb 21.

Biozentrum, University of Basel, Basel, Switzerland

Low-carbohydrate/high-fat (LCHF) diets are increasingly popular dietary interventions for body weight control and as treatment for different pathological conditions. However, the mechanisms of action are still poorly understood, in particular, in long-term administration. Besides liver, brain, and heart, skeletal muscle is one of the major organs involved in the regulation of physiological and pathophysiological ketosis. We assessed the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle of male wild-type control and PGC-1α muscle-specific knockout mice upon 12 wk of LCHF diet feeding. Interestingly, LCHF diet administration increased oxygen consumption in a muscle PGC-1α-dependent manner, concomitant with a blunted transcriptional induction of genes involved in fatty acid oxidation and impairment in exercise performance. These data reveal a new role for muscle PGC-1α in regulating the physiological adaptation to long-term LCHF diet administration.
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http://dx.doi.org/10.1152/ajpendo.00361.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451528PMC
May 2017

Human Muscle Precursor Cells Overexpressing PGC-1α Enhance Early Skeletal Muscle Tissue Formation.

Cell Transplant 2017 06 3;26(6):1103-1114. Epub 2017 Feb 3.

Muscle precursor cells (MPCs) are activated satellite cells capable of muscle fiber reconstruction. Therefore, autologous MPC transplantation is envisioned for the treatment of muscle diseases. However, the density of MPCs, as well as their proliferation and differentiation potential, gradually declines with age. The goals of this research were to genetically modify human MPCs (hMPCs) to overexpress the peroxisome proliferator-activated receptor γ coactivator (PGC-1α), a key regulator of exercise-mediated adaptation, and thereby to enhance early skeletal muscle formation and quality. We were able to confirm the sustained myogenic phenotype of the genetically modified hMPCs. While maintaining their viability and proliferation potential, PGC-1α-modified hMPCs showed an enhanced myofiber formation capacity in vitro. Engineered muscle tissues were harvested 1, 2, and 4 weeks after subcutaneous injection of cell-collagen suspensions, and histological analysis confirmed the earlier myotube formation in PGC-1α-modified samples, predominantly of slow-twitch myofibers. Increased contractile protein levels were detected by Western blot. In summary, by genetically modifying hMPCs to overexpress PGC-1α, we were able to promote early muscle fiber formation in vitro and in vivo, with an initial switch to slow-type myofibers. Therefore, overexpressing PGC-1α is a novel strategy to further enhance skeletal muscle tissue engineering.
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http://dx.doi.org/10.3727/096368917X694868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469437PMC
June 2017

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP.

Sci Rep 2017 01 16;7:40789. Epub 2017 Jan 16.

Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, CH-4056 Basel, Switzerland.

Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches.
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http://dx.doi.org/10.1038/srep40789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5238507PMC
January 2017

Coregulator-mediated control of skeletal muscle plasticity - A mini-review.

Biochimie 2017 May 3;136:49-54. Epub 2017 Jan 3.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland. Electronic address:

Skeletal muscle plasticity is a complex process entailing massive transcriptional programs. These changes are mediated by the action of nuclear receptors and other transcription factors. In addition, coregulator proteins have emerged as important players in this process by linking transcription factors to the RNA polymerase II complex and inducing changes in the chromatic structure. An accumulating body of work highlights the pleiotropic functions of coregulator proteins in the control of tissue-specific and whole body metabolism. In skeletal muscle, several coregulators have been identified as potent modulators of metabolic and myofibrillar plasticity. In this mini-review, we will discuss the control, function and physiological significance of these coregulators in skeletal muscle biology.
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http://dx.doi.org/10.1016/j.biochi.2016.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453242PMC
May 2017

Muscle PGC-1α modulates satellite cell number and proliferation by remodeling the stem cell niche.

Skelet Muscle 2016 12 2;6(1):39. Epub 2016 Dec 2.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056, Basel, Switzerland.

Background: The myogenic capacity of satellite cells (SCs), adult muscle stem cells, is influenced by aging, exercise, and other factors. In skeletal muscle, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulator of oxidative metabolism and endurance training adaptation. However, a link between PGC-1α and SC behavior remains unexplored.

Methods: We have now studied SC function in a PGC-1α fiber-specific gain-of-function animal model.

Results: In surprising contrast to bona fide exercise, muscle-specific PGC-1α transgenic mice have lower SC numbers. Nevertheless, SCs from these mice have a higher propensity for activation and proliferation. Intriguingly, muscle PGC-1α triggers a remodeling of the SC niche by altering the extracellular matrix composition, including the levels of fibronectin, which affects the proliferative output of SCs.

Conclusions: Taken together, PGC-1α indirectly affects SC plasticity in skeletal muscle and thereby might contribute to improved SC activation in exercise.
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http://dx.doi.org/10.1186/s13395-016-0111-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134094PMC
December 2016

Exploring the Role of PGC-1α in Defining Nuclear Organisation in Skeletal Muscle Fibres.

J Cell Physiol 2017 Jun 29;232(6):1270-1274. Epub 2016 Dec 29.

Centre of Human and Aerospace Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Muscle fibres are multinucleated cells, with each nucleus controlling the protein synthesis in a finite volume of cytoplasm termed the myonuclear domain (MND). What determines MND size remains unclear. In the present study, we aimed to test the hypothesis that the level of expression of the transcriptional coactivator PGC-1α and subsequent activation of the mitochondrial biogenesis are major contributors. Hence, we used two transgenic mouse models with varying expression of PGC-1α in skeletal muscles. We isolated myofibres from the fast twitch extensor digitorum longus (EDL) and slow twitch diaphragm muscles. We then membrane-permeabilised them and analysed the 3D spatial arrangements of myonuclei. In EDL muscles, when PGC-1α is over-expressed, MND volume decreases; whereas, when PGC-1α is lacking, no change occurs. In the diaphragm, no clear difference was noted. This indicates that PGC-1α and the related mitochondrial biogenesis programme are determinants of MND size. PGC-1α may facilitate the addition of new myonuclei in order to reach MND volumes that can support an increased mitochondrial density. J. Cell. Physiol. 232: 1270-1274, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326684PMC
June 2017

PGC-1α modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle.

Skelet Muscle 2016 8;6:38. Epub 2016 Nov 8.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland.

Background: Skeletal muscle tissue has an enormous regenerative capacity that is instrumental for a successful defense against muscle injury and wasting. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) exerts therapeutic effects in several muscle pathologies, but its role in damage-induced muscle regeneration is unclear.

Methods: Using muscle-specific gain- and loss-of-function models for PGC-1α in combination with the myotoxic agent cardiotoxin (CTX), we explored the role of this transcriptional coactivator in muscle damage and inflammation.

Results: Interestingly, we observed PGC-1α-dependent effects at the early stages of regeneration, in particular regarding macrophage accumulation and polarization from the pro-inflammatory M1 to the anti-inflammatory M2 type, a faster resolution of necrosis and protection against the development of fibrosis after multiple CTX-induced injuries.

Conclusions: PGC-1α exerts beneficial effects on muscle inflammation that might contribute to the therapeutic effects of elevated muscle PGC-1α in different models of muscle wasting.
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http://dx.doi.org/10.1186/s13395-016-0110-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101792PMC
October 2017