Publications by authors named "Gesa Santos"

12 Publications

  • Page 1 of 1

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

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

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

PGC-1α expression in murine AgRP neurons regulates food intake and energy balance.

Mol Metab 2016 Jul 18;5(7):580-588. Epub 2016 May 18.

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

Objective: Food intake and whole-body energy homeostasis are controlled by agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus of the hypothalamus. Key energy sensors, such as the AMP-activated protein kinase (AMPK) or sirtuin 1 (SIRT1), are essential in AgRP and POMC cells to ensure proper energy balance. In peripheral tissues, the transcriptional coactivator PGC-1α closely associates with these sensors to regulate cellular metabolism. The role of PGC-1α in the ARC nucleus, however, remains unknown.

Methods: Using AgRP and POMC neurons specific knockout (KO) mouse models we studied the consequences of PGC-1α deletion on metabolic parameters during fed and fasted states and on ghrelin and leptin responses. We also took advantage of an immortalized AgRP cell line to assess the impact of PGC-1α modulation on fasting induced AgRP expression.

Results: PGC-1α is dispensable for POMC functions in both fed and fasted states. In stark contrast, mice carrying a specific deletion of PGC-1α in AgRP neurons display increased adiposity concomitant with significantly lower body temperature and RER values during nighttime. In addition, the absence of PGC-1α in AgRP neurons reduces food intake in the fed and fasted states and alters the response to leptin. Finally, both in vivo and in an immortalized AgRP cell line, PGC-1α modulates AgRP expression induction upon fasting.

Conclusions: Collectively, our results highlight a role for PGC-1α in the regulation of AgRP neuronal functions in the control of food intake and peripheral metabolism.
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http://dx.doi.org/10.1016/j.molmet.2016.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921790PMC
July 2016

The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet.

Diabetologia 2014 Nov 13;57(11):2405-12. Epub 2014 Aug 13.

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

Aims/hypothesis: Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo.

Methods: Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining.

Results: Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α-PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle.

Conclusions/interpretation: Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.
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http://dx.doi.org/10.1007/s00125-014-3352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657154PMC
November 2014

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling.

Proc Natl Acad Sci U S A 2013 Dec 25;110(50):20314-9. Epub 2013 Nov 25.

Biozentrum, University of Basel, 4056 Basel, Switzerland.

Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.
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http://dx.doi.org/10.1073/pnas.1312039110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864298PMC
December 2013

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.

Proc Natl Acad Sci U S A 2013 May 6;110(21):8738-43. Epub 2013 May 6.

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

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.
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http://dx.doi.org/10.1073/pnas.1212976110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666691PMC
May 2013

PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner.

Diabetes 2013 Jan 18;62(1):85-95. Epub 2012 Oct 18.

1Biozentrum, Division of Pharmacology/Neurobiology, University of Basel, Basel, Switzerland.

Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders.
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http://dx.doi.org/10.2337/db12-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526021PMC
January 2013

Remodeling of calcium handling in skeletal muscle through PGC-1α: impact on force, fatigability, and fiber type.

Am J Physiol Cell Physiol 2012 Jan 14;302(1):C88-99. Epub 2011 Sep 14.

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

Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.
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http://dx.doi.org/10.1152/ajpcell.00190.2011DOI Listing
January 2012

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity.

Biochem Biophys Res Commun 2011 Apr 8;408(1):180-5. Epub 2011 Apr 8.

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

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1α on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1α in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1α induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1α enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1α boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1α coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, over-expression of PGC-1α does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1α mimic the beneficial effects of endurance training on muscle metabolism in this context.
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http://dx.doi.org/10.1016/j.bbrc.2011.04.012DOI Listing
April 2011

Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) promotes skeletal muscle lipid refueling in vivo by activating de novo lipogenesis and the pentose phosphate pathway.

J Biol Chem 2010 Oct 17;285(43):32793-800. Epub 2010 Aug 17.

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

Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). PGC-1α enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1α levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1α-mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1α and human muscle biopsies pre- and post-exercise. We demonstrate that PGC-1α enhances lipogenesis in skeletal muscle through liver X receptor α-dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1α and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1α coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.
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http://dx.doi.org/10.1074/jbc.M110.145995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963391PMC
October 2010

Effect of calpain and proteasome inhibition on Ca2+-dependent proteolysis and muscle histopathology in the mdx mouse.

FASEB J 2008 Dec 26;22(12):4190-200. Epub 2008 Aug 26.

Santhera Pharmaceuticals (Switzerland) Ltd, Hammerstrasse 47, CH-4410 Liestal, Switzerland.

Dystrophin deficiency is the underlying molecular cause of progressive muscle weakness observed in Duchenne muscular dystrophy (DMD). Loss of functional dystrophin leads to elevated levels of intracellular Ca(2+), a key step in the cellular pathology of DMD. The cysteine protease calpain is activated in dystrophin-deficient muscle, and its inhibition is regarded as a potential therapeutic approach. In addition, previous work has shown that the ubiquitin-proteasome system also contributes to muscle protein breakdown in dystrophic muscle and, therefore, also qualifies as a potential target for therapeutic intervention in DMD. The relative contribution of calpain- and proteasome-mediated proteolysis induced by increased Ca(2+) levels was characterized in cultured muscle cells and revealed initial Ca(2+) influx-dependent calpain activity and subsequent Ca(2+)-independent activity of the ubiquitin-proteasome system. We then set out to optimize novel small-molecule inhibitors that inhibit both calpain as well as the 20S proteasome in a cellular system with impaired Ca(2+) homeostasis. On administration of such inhibitors to mdx mice, quantitative histological parameters improved significantly, in particular with compounds strongly inhibiting the 20S proteasome. To investigate the role of calpain inhibition without interfering with the ubiquitin-proteasome system, we crossed mdx mice with transgenic mice, overexpressing the endogenous calpain inhibitor calpastatin. Although our data show that proteolysis by calpain is strongly inhibited in the transgenic mdx mouse, this calpain inhibition did not ameliorate muscle histology. Our results indicate that inhibition of the proteasome rather than calpain is required for histological improvement of dystrophin-deficient muscle. In conclusion, we have identified novel proteasome inhibitors that qualify as potential candidates for pharmacological intervention in muscular dystrophy.
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http://dx.doi.org/10.1096/fj.07-099036DOI Listing
December 2008