Publications by authors named "Florian Schaerer"

4 Publications

  • Page 1 of 1

Loss of skeletal muscle strength by ablation of the sarcoplasmic reticulum protein JP45.

Proc Natl Acad Sci U S A 2007 Dec 5;104(50):20108-13. Epub 2007 Dec 5.

Departments of Anaesthesia and Research, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.

Skeletal muscle constitutes approximately 40% of the human body mass, and alterations in muscle mass and strength may result in physical disability. Therefore, the elucidation of the factors responsible for muscle force development is of paramount importance. Excitation-contraction coupling (ECC) is a process during which the skeletal muscle surface membrane is depolarized, causing a transient release of calcium from the sarcoplasmic reticulum that activates the contractile proteins. The ECC machinery is complex, and the functional role of many of its protein components remains elusive. This study demonstrates that deletion of the gene encoding the sarcoplasmic reticulum protein JP45 results in decreased muscle strength in young mice. Specifically, this loss of muscle strength in JP45 knockout mice is caused by decreased functional expression of the voltage-dependent Ca(2+) channel Ca(v)1.1, which is the molecule that couples membrane depolarization and calcium release from the sarcoplasmic reticulum. These results point to JP45 as one of the molecules involved in the development or maintenance of skeletal muscle strength.
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http://dx.doi.org/10.1073/pnas.0707389104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148430PMC
December 2007

Asymmetric recruitment of dynein to spindle poles and microtubules promotes proper spindle orientation in yeast.

Dev Cell 2006 Apr;10(4):425-39

Institute of Biochemistry, Biology Department, Swiss Federal Institute of Technology, ETH Zürich, 8093 Zürich, Switzerland.

The orientation of the mitotic spindle plays a key role in determining whether a polarized cell will divide symmetrically or asymmetrically. In most cell types, cytoplasmic dynein plays a critical role in spindle orientation. However, how dynein directs opposite spindle poles toward distinct and predetermined cell ends is poorly understood. Here, we show that dynein distributes preferentially to the spindle pole bodies (SPB) and astral microtubules (MTs) proximal to the bud in metaphase yeast cells. Dynein asymmetry depended on the bud neck kinases Elm1, Hsl1, and Gin4, on the spindle pole components Cnm67 and Cdk1, and on the B-type cyclins Clb1 and Clb2. Furthermore, phenotypic and genetic studies both indicated that dynein is unable to orient the spindle when it localizes to both poles and associated microtubules. Together, our data indicate that proper orientation of the spindle requires dynein to act on a single spindle pole.
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http://dx.doi.org/10.1016/j.devcel.2006.02.018DOI Listing
April 2006

Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice.

J Pharmacol Exp Ther 2006 May 25;317(2):771-7. Epub 2006 Jan 25.

Applied Pharmacology, Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.

Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed. Melanocortin 4-receptor (MC4-R) blockade has been shown recently to be effective in preventing cancer cachexia in rodent models. In the present study, we have tested a MC4-R blocker, ML00253764 [2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazolium hydrochloride] (Vos et al., 2004), in vitro and in vivo. In membranes of human embryonic kidney 293 cells expressing human MC4-R, ML00253764 displaced [Nle(4), d-Phe(7)]-alpha-melanocyte-stimulating hormone binding with an IC(50) of 0.32 microM. At concentrations above 1 microM, ML00253764 decreased cAMP accumulation (maximal reduction of -20%) indicative of inverse agonist activity. ML00253764 was administered twice daily (15 mg/kg s.c.) for 13 days to C57BL6 mice bearing s.c. Lewis lung carcinoma tumors. Food intake and body weight were measured, and body composition was assessed using magnetic resonance relaxometry. ML00253764 stimulated light-phase food intake relative to vehicle-treated controls (p < 0.05), although no effect was observed on 24-h food intake. During the 21 days of the experiment, the LBM of tumor vehicle-treated mice decreased (p < 0.05). In contrast, the tumor-bearing mice treated with ML00253764 maintained their LBM. These data support the view that MC4-R blockade may be a suitable approach for the treatment of cancer cachexia and that MC4-R inverse agonists may have potential as drug candidates.
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http://dx.doi.org/10.1124/jpet.105.097725DOI Listing
May 2006

Reorientation of mispositioned spindles in short astral microtubule mutant spc72Delta is dependent on spindle pole body outer plaque and Kar3 motor protein.

Mol Biol Cell 2002 Apr;13(4):1366-80

Lehrstuhl für Angewandte Mikrobiologie, Biozentrum, Universität Basel, CH-4056 Basel, Switzerland.

Nuclear migration and positioning in Saccharomyces cerevisiae depend on long astral microtubules emanating from the spindle pole bodies (SPBs). Herein, we show by in vivo fluorescence microscopy that cells lacking Spc72, the SPB receptor of the cytoplasmic gamma-tubulin complex, can only generate very short (<1 microm) and unstable astral microtubules. Consequently, nuclear migration to the bud neck and orientation of the anaphase spindle along the mother-bud axis are absent in these cells. However, SPC72 deletion is not lethal because elongated but misaligned spindles can frequently reorient in mother cells, permitting delayed but otherwise correct nuclear segregation. High-resolution time-lapse sequences revealed that this spindle reorientation was most likely accomplished by cortex interactions of the very short astral microtubules. In addition, a set of double mutants suggested that reorientation was dependent on the SPB outer plaque and the astral microtubule motor function of Kar3 but not Kip2/Kip3/Dhc1, or the cortex components Kar9/Num1. Our observations suggest that Spc72 is required for astral microtubule formation at the SPB half-bridge and for stabilization of astral microtubules at the SPB outer plaque. In addition, our data exclude involvement of Spc72 in spindle formation and elongation functions.
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http://dx.doi.org/10.1091/mbc.01-07-0338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC102275PMC
April 2002