| 1. |
- Larsson, Lars, 1952-, et al.
(author)
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Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease
- 2008
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In: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 295:3, s. 722-731
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Journal article (peer-reviewed)abstract
- Slow troponin T (TnT) plays an indispensable role in skeletal muscle function. Alternative RNA splicing in the NH2-terminal region produces high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms of slow TnT. Normal adult slow muscle fibers express mainly HMW slow TnT. Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral polyneuropathies caused by various neuronal defects. We found in the present study that LMW slow TnT was significantly upregulated in demyelination form type 1 CMT (CMT1) but not axonal form type 2 CMT (CMT2) muscles. Contractility analysis showed an increased specific force in single fibers isolated from CMT1 but not CMT2 muscles compared with control muscles. However, an in vitro motility assay showed normal velocity of the myosin motor isolated from CMT1 and CMT2 muscle biopsies, consistent with their unchanged myosin isoform contents. Supporting a role of slow TnT isoform regulation in contractility change, LMW and HMW slow TnT isoforms showed differences in the molecular conformation in conserved central and COOH-terminal regions with changed binding affinity for troponin I and tropomyosin. In addition to providing a biochemical marker for the differential diagnosis of CMT, the upregulation of LMW slow TnT isoforms under the distinct pathophysiology of CMT1 demonstrates an adaptation of muscle function to neurological disorders by alternative splicing modification of myofilament proteins.
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| 2. |
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| 3. |
- Lionikas, Arimantas, et al.
(author)
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Genomic Analysis of Variation in Hindlimb Musculature of Mice from the C57BL/6J and DBA/2J Lineage
- 2010
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In: Journal of Heredity. - : Oxford University Press (OUP). - 0022-1503 .- 1465-7333. ; 101:3, s. 360-367
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Journal article (peer-reviewed)abstract
- The precise locations of attachment points of muscle to bone-the origin and insertion sites-are crucial anatomical and functional characteristics that influence locomotor performance. Mechanisms that control the development of these interactions between muscle, tendon, and bone are currently not well understood. In a subset of BXD recombinant inbred (RI) strains derived from the C57BL/6J and DBA/2J strains, we observed a soleus femoral attachment anomaly (SFAA) that was rare in both parental strains (Lionikas, Glover et al. 2006). The aim of the present study was to assess suitability of SFAA as a model to study the genetic mechanisms underlying variation in musculoskeletal anatomy. We scored the incidence of SFAA in 55 BXD strains (n = 9 to 136, median = 26, phenotyped animals per strain, for a total number of 2367). Seven strains (BXD1, 12, 38, 43, 48, 54, and 56) exhibited a high incidence of unilateral SFAA (47-89%), whereas 23 strains scored 0%. Exploration of the mechanisms underlying SFAA in 2 high incidence strains, BXD1 and BXD38, indicated that SFAA-relevant genes are to be found in both C57BL/6J and DBA/2J regions of the BXD1 genome. However, not all alleles relevant for the expression of the phenotype were shared between the 2 high-incidence BXD strains. In conclusion, the anatomical origin of the soleus muscle in mouse is controlled by a polygenic system. A panel of BXD RI strains is a useful tool in exploring the genetic mechanisms underlying SFAA and improving our understanding of musculoskeletal development.
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| 4. |
- Yu, Fushun
(author)
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Adaptability of skeletal muscle to hormone treatment in relation to gender and aging
- 1999
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Doctoral thesis (other academic/artistic)abstract
- The aims of this study were to investigate the expression of myosin isoforms, muscle contractility at the cell level, and changes in these parameters in response to altered hormonal status in aging male and female rodents. In addition, by using mice lacking thyroid hormone receptors (TR[alpha]1 or TR[beta] or TR[alpha]1/[beta]) we tried to improve our understanding of the mechanisms by which thyroid hormone regulates the expression of specific MyHC isoforms via these different nuclear receptors. The enzyme-histochemical characteristics showed that 4 weeks of l treatment induced a significant decrease in the number of type I fibers and an increase in the number of type IC and IIC fibers in the soleus, irrespective of gender and age. In the EDL, T3 treatment resulted in a significant type IIA to type IIB fiber transition in both young and old female rats, but no changes were observed in the male rats. TR[alpha]1-/- or TR[alpha]1- /-[beta]-/-mice significantly increased the number of type I fibers and decreased type IIA fibers. The proportions of type I and type IIA fibers did not change in TR[beta] -/- mice. High-sensitive 7% SDS-PAGE analysis of MyHC isoform composition confirmed and extended the enzyme-histochemical results. That is, a significant down-regulation of the type I MyHC and an up-regulation of type IIA MyHC were observed in muscles from hyperthyroid rats, irrespective of gender. However, the upregulation of the IIX MyHC was more pronounced in male than in female rats both at the single-fiber and whole-muscle levels, irrespective of age. The expression of MyHC isoforms in females was more variable than that in males, i.e., type IIAX fibers, type I/IIAX fibers, [alpha] cardiac-like fibers and [alpha] cardiac-like/IIA fibers were found. In the EDL, the age-related type IIB to IIX MyHC isoform switching was found in both male and female rats, i.e., the type IIX MyHC content was higher and the type IIB content lower in old rats of both sexes. In the females, T3 treatment decreased the type IIA MyHC content and increased type IIB MyHC content in both young and old rats. In the males, on the other hand, T3 treatment had no significant influence on the expression of the different fast MyHC isoforms, in spite of the fact that type IIA mRNA has been reported to be downregulated in both males and females. The different expression of MyHCs in the EDL muscle of males and females in response to T3 treatment raises the possibility of a gender-related difference in the translational regulation of MyHC isoforms by thyroid hormone. At the single-fiber level, an age-related slowing of maximum velocity of unloaded shortening (V0) was observed in the soleus muscle of rats in both genders. Four weeks of T3 treatment induced a stronger upregulation of the fast MyHC IIA, MyLCf1 and MyLCf2 isoforms from soleus muscle fibers in females than in those of males. Concomitantly, the V0 of the pooled fibers was higher in female than in male hyperthyroid rats regardless of animal age in soleus fibers. Further, in the female hyperthyroid rats, V0 of the fibers expressing [beta]/slow (type I) MyHC was significantly higher, compared with those in control rats of both the young and the old; the differences between male and female hyperthyroid soleus muscles are suggested to be related to an interaction of thyroid hormone and sex hormones in the regulation of myosin gene expression. Disuption of thyroid hormone receptors TR[alpha]1 or TR[beta] or both receptors induced transitions of MyHC isoforms; i.e., in EDL muscle, the TR deficiency induced a significant decrease in type IIB MyHC. In the soleus, a significant up-regulation of type I MyHC and a down-regulation of type IIA MyHC were observed in TR[alpha]1-/-[beta]-/- and TR[alpha]1-/- mice. The extent of the deficient effect was highly dependent on the type of receptor deleted. The lack of TR[beta] had no significant effect on the expression of MyHC isoforms. A moderate type I MyHC increase was observed in the TR[alpha]1-/-mice, while a dramatic over-expression of the slow myosin isoform (type I MyHC), and a corresponding down-regulation of the fast type IIA MyHC were observed in TR[alpha]1-/-[beta]-/- mice. Embryonic or fetal MyHC isoforms were not expressed in either soleus or EDL from different TR deficient mice, indicating that the developmental transition from embryonic or fetal MyHC isoforms is not solely related to an effect of T3 via TRs. These results suggest that either TR[alpha]1 or TR[beta] is able to functionally substitute for, or co-operate with, each other, and emphasize the complex interaction between TRs and other cell- and muscle-type specific factors, which play a very important role in the developmental transition from embryonic or fetal MyHC to adult MyHC isoforms.
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| 5. |
- Yu, Fushun, et al.
(author)
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Effects of ageing and gender on contractile properties in human skeletal muscle and single fibres
- 2007
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In: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 190:3, s. 229-241
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Journal article (peer-reviewed)abstract
- Aim: The objective of this study is to improve our understanding of the mechanisms underlying the ageing- and gender-related muscle weakness. Methods: Ageing- and gender-related differences in regulation of muscle contraction have been studied in knee-extensor muscles at the whole muscle and single muscle fibre levels in young and old sedentary men and women. In vivo knee-extensor muscle function was measured at slow (30° s−1) and faster (180 ° s−1) speeds of movement. Maximum velocity of unloaded shortening (V0) and maximum force normalized to cross-sectional area (CSA) [specific tension (ST)] were measured in single 'skinned' skeletal muscle fibre segments. Results: Significant ageing- and gender-related differences were observed in muscle torque. A 33–55% ageing-related decline (P < 0.001) in maximum torque was observed irrespective of gender. At the single muscle fibre level, the ageing-related decline in knee-extensor muscle function was accompanied by a 20–28% decline in ST in muscle fibres expressing the type I MyHC isoform in both men and women, and a 29% decline in type IIa muscle fibre CSA, but the decreased fast-twitch fibre size was restricted to the men. Furthermore, in both men and women, V0 decreased in muscle cells expressing the type I and IIa MyHC isoforms. Conclusion: The present results provide evidence of specific ageing- and gender-related differences in regulation of muscle contraction at the cellular level. It is suggested that these cellular changes have a significant impact on muscle function and the ageing-related motor handicap.
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