Acute molecular response of mouse hindlimb muscles to chronic stimulation

Dept. of Pathology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Shadyside Hospital West Wing, WG02.11, 5230 Center Ave., Pittsburgh, PA 15232, USA.
AJP Cell Physiology (Impact Factor: 3.78). 08/2009; 297(3):C556-70. DOI: 10.1152/ajpcell.00046.2009
Source: PubMed


Stimulation of the mouse hindlimb via the sciatic nerve was performed for a 4-h period to investigate acute muscle gene activation in a model of muscle phenotype conversion. Initial force production (1.6 +/- 0.1 g/g body wt) declined 45% within 10 min and was maintained for the remainder of the experiment. Force returned to initial levels upon study completion. An immediate-early growth response was present in the extensor digitorum longus (EDL) muscle (FOS, JUN, activating transcription factor 3, and musculoaponeurotic fibrosarcoma oncogene) with a similar but attenuated pattern in the soleus muscle. Transcript profiles showed decreased fast fiber-specific mRNA (myosin heavy chains 2A and 2B, fast troponins T(3) and I, alpha-tropomyosin, muscle creatine kinase, and parvalbumin) and increased slow transcripts (myosin heavy chain-1beta/slow, troponin C slow, and tropomyosin 3y) in the EDL versus soleus muscles. Histological analysis of the EDL revealed glycogen depletion without inflammatory cell infiltration in stimulated versus control muscles, whereas ultrastructural analysis showed no evidence of myofiber damage after stimulation. Multiple fiber type-specific transcription factors (tea domain family member 1, nuclear factor of activated T cells 1, peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -beta, circadian locomotor output cycles kaput, and hypoxia-inducible factor-1alpha) increased in the EDL along with transcription factors characteristic of embryogenesis (Kruppel-like factor 4; SRY box containing 17; transcription factor 15; PBX/knotted 1 homeobox 1; and embryonic lethal, abnormal vision). No established in vivo satellite cell markers or genes activated in our parallel experiments of satellite cell proliferation in vitro (cyclins A(2), B(2), C, and E(1) and MyoD) were differentially increased in the stimulated muscles. These results indicated that the molecular onset of fast to slow phenotype conversion occurred in the EDL within 4 h of stimulation without injury or satellite cell recruitment. This conversion was associated with the expression of phenotype-specific transcription factors from resident fiber myonuclei, including the activation of nascent developmental transcriptional programs.

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    • "We have identified the Pbx/Knotted homeobox binding site in the promoter region of a number of upregulated genes. This agrees with the finding in skeletal muscle, in which chronic hypoxia leads to conversion of fast to slow fibers with increased expression of Pbx/Knotted homeobox [59]. Pbx also has been shown to be involved in cardiac muscle differentiation [60]. "
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    PLoS ONE 12/2013; 8(12):e82200. DOI:10.1371/journal.pone.0082200 · 3.23 Impact Factor
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    • "α- and β-Tm isoforms are characteristic of fast-twitch muscles and we found only these isoforms in the control muscles. In contrast, 8-week diabetic muscle samples in addition to the α- and β-Tm isoforms contained the γ-Tm isoform, which is only found in slow-twitch muscle fibers [19]. While this is not a thorough analysis of isoforms changes in the contractile and regulatory proteins under these conditions, the studies of Zhi et al. [17] suggest that an increase in the γ-Tm isoform would be accompanied by an increase in the myosin heavy chain isoforms I and IIa, a decrease in the myosin heavy chain isoforms IIb and IIx, and a switch from fast to slow isoforms of Troponin I and Troponin T. Therefore, it would appear that at least part of the compensation observed at 4 and 8 weeks of diabetes is due to a certain degree of fiber-type switching. "
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    Journal of Jilin University Medicine Edition 11/2009; 35(6):1092-1096.
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