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Gene and protein expression in denervated atrophic and hypertrophic skeletal muscle
Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Following denervation skeletal muscles change their functional and structural properties. Some changes resemble conditions in developing muscles and may be important for reinnervation. Due to inactivity following denervation most skeletal muscles loose muscle mass and become atrophic. The hemidiaphragm muscle, however, undergoes a phase of transient hypertrophy following denervation, gaining weight during the first 6-10 days followed by a decrease in weight. In this thesis the expression (mRNA, protein and protein phosphorylations) of potential factors involved in the regulation of muscle mass were examined in denervated hind-limb and hemidiaphragm muscles.

NIFK is a protein that associates with Ki67, a protein expressed predominantly in proliferating cells. The mRNA expression of NIFK was upregulated in denervated atrophic muscles but unaltered in denervated hypertrophic muscles, suggesting a potential role in the regulation of skeletal muscle mass (Paper I). p38 MAPK has previously been implicated in both anabolic and catabolic processes. Its substrate MK2 becomes phosphorylated at two sites, one of which is suggested to be important for nuclear export. MK2 phosphorylation at this site correlated with muscle weight in both atrophic and hypertrophic denervated muscles and may thus have a role in atrophy and hypertrophy (Paper III). Factors regulating protein synthesis are likely to play a role in atrophy and hypertrophy and many signaling pathways appear to converge on the formation of the translation initiation complex. The protein expression and phosphorylation status of several components in both Wnt and Akt signaling pathways indicate increased protein synthesis in denervated atrophic muscles as well as in denervated hypertrophic muscles (Papers II, IV and V). This suggests that increased protein degradation is more important than decreased protein synthesis for the loss of muscle mass in denervated atrophic muscles.

Place, publisher, year, edition, pages
Växjö, Kalmar: Linnaeus University Press , 2011.
Series
Linnaeus University Dissertations, 34/2011
Keyword [en]
Skeletal muscle, Denervation, Hypertrophy, Atrophy, Gene expression, Protein expression, Protein phosphorylation, NIFK, Wnt, MK2, Akt signaling
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:lnu:diva-10411ISBN: 978-91-86491-61-1 (print)OAI: oai:DiVA.org:lnu-10411DiVA: diva2:393004
Public defence
2011-03-11, N2007, Smålandsgatan 24, Kalmar, 09:00 (Swedish)
Supervisors
Available from: 2011-01-31 Created: 2011-01-28 Last updated: 2014-05-09Bibliographically approved
List of papers
1. The nifk gene is widely expressed in mouse tissues and is up-regulated in denervated hind limb muscle
Open this publication in new window or tab >>The nifk gene is widely expressed in mouse tissues and is up-regulated in denervated hind limb muscle
2003 (English)In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 27, no 6, 469-475 p.Article in journal (Refereed) Published
Abstract [en]

Denervation of skeletal muscle alters the expression of many genes, which may be important for establishing optimal conditions for reinnervation. Using the differential display technique we have attempted to discover neurally regulated genes in skeletal muscle. An mRNA that is up-regulated in denervated hind limb muscle was identified and cloned. The cDNA encodes an RNA-binding protein, which was discovered during the course of this work to be a nucleolar protein interacting with the fork-head associated domain of the proliferation marker protein Ki-67, and named NIFK. We show that the nifk gene is widely expressed in adult mouse tissues and that the expression is up-regulated in denervated hind limb muscle. No difference between expression in perisynaptic and extrasynaptic portions of muscle was observed. The widespread expression in adult tissues suggests that the NIFK protein has other functions in addition to its interaction with Ki-67, which is only expressed in proliferating cells.

National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology; Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-343 (URN)10.1016/S1065-6995(03)00038-6 (DOI)
Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2011-02-10Bibliographically approved
2. Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle.
Open this publication in new window or tab >>Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle.
2008 (English)In: Journal of Molecular Histology, ISSN 1567-2379, Vol. 39, no 3, 329-337 p.Article in journal (Refereed) Published
Abstract [en]

Wnts are secreted proteins with functions in differentiation, development and cell proliferation. Wnt signaling has also been implicated in neuromuscular junction formation and may function in synaptic plasticity in the adult as well. Secreted frizzled-related proteins (Sfrps) such as Sfrp1 can function as inhibitors of Wnt signaling. In the present study a potential role of Wnt signaling in denervation was examined by comparing the expression levels of Sfrp1 and key proteins in the canonical Wnt pathway, Dishevelled, glycogen synthase kinase 3 beta and beta-catenin, in innervated and denervated rodent skeletal muscle. Sfrp1 mRNA and immunoreactivity were found to be up-regulated in mouse hemidiaphragm muscle following denervation. Immunoreactivity, detected by Western blots, and mRNA, detected by Northern blots, were both expressed in extrasynaptic as well as perisynaptic parts of the denervated muscle. Immunoreactivity on tissue sections was, however, found to be concentrated postsynaptically at neuromuscular junctions. Using beta-catenin levels as a readout for canonical Wnt signaling no evidence for decreased canonical Wnt signaling was obtained in denervated muscle. A role for Sfrp1 in denervated muscle, other than interfering with canonical Wnt signaling, is discussed.

National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-1721 (URN)10.1007/s10735-008-9169-y (DOI)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2013-07-24Bibliographically approved
3. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) in skeletal muscle atrophy and hypertrophy
Open this publication in new window or tab >>Mitogen-activated protein kinase-activated protein kinase 2 (MK2) in skeletal muscle atrophy and hypertrophy
2010 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 223, no 1, 194-201 p.Article in journal (Refereed) Published
Abstract [en]

Skeletal muscle is a highly plastic tissue. Overall muscle growth (hypertrophy) or muscle wasting (atrophy) results from alterations in intracellular signaling pathways with important regulatory steps occurring in the nucleus as well as in the cytoplasm. Previous studies have identified components of the Akt/mTor pathway as well as the p38 MAPK pathway as important for skeletal muscle hypertrophy and/or atrophy. The present study tests the hypothesis that MK2, a substrate of p38 which following phosphorylation, can be exported from the nucleus in a complex with p38, may be important for skeletal muscle growth. The expression of MK2 was examined in denervated mouse hind-limb (atrophic) and hemidiaphragm (transiently hypertrophic) muscles. MK2 mRNA expression decreased after denervation in both atrophic (48% of innervated controls, P < 0.001) and hypertrophic muscle (34% of innervated controls, P < 0.01) but MK2 protein expression decreased only in atrophic muscle (32% of innervated controls, P < 0.01). The level of T205 phosphorylated MK2 increased after denervation in both atrophic (fourfold increase, P < 0.01) and hypertrophic muscles (almost sevenfold increase, P < 0.001) whereas the level of T317 phosphorylated MK2 (necessary for nuclear export) increased after denervation in hypertrophic muscle (nearly threefold increase, P < 0.001) but not in atrophic muscle. Logarithmically transformed relative changes in MK2 phosphorylated at T317 correlated well (r2 = 0.7737) with relative changes in muscle weight. The results suggest a role for MK2 in the regulation of muscle mass, a role which, at least in part, may be related to determining the subcellular localization of p38 in muscle fibers. J. Cell. Physiol. 223: 194–201,

Place, publisher, year, edition, pages
Wiley-Liss, Inc., 2010
National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology; Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-2134 (URN)10.1002/jcp.22023 (DOI)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2011-01-31Bibliographically approved

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