Hannah C Lincoln

University of Wisconsin–Madison, Madison, Wisconsin, United States

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Publications (5)23.1 Total impact

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    ABSTRACT: The activation of mTOR signaling is essential for mechanically-induced changes in skeletal muscle mass, and previous studies have suggested that mechanical stimuli activate mTOR signaling through a phospholipase D (PLD)-dependent increase in the concentration of phosphatidic acid ([PA]). Consistent with this conclusion, we obtained evidence which further suggests that mechanical stimuli utilize PA as a direct upstream activator of mTOR signaling. Unexpectedly though, we found that the activation of PLD is not necessary for the mechanically-induced increases in [PA] or mTOR signaling. Motivated by this observation, we performed experiments that were aimed at identifying the enzyme(s) that promote the increase in [PA]. These experiments revealed that mechanical stimulation increases the concentration of diacylglycerol (DAG) and the activity of DAG kinases (DGKs) in membranous structures. Furthermore, using knockout mice, we determined that the zeta isoform of DGK (DGKζ) is necessary for the mechanically-induced increase in [PA]. We also determined that DGKζ significantly contributes to the mechanical activation of mTOR signaling and this is likely driven by an enhanced binding of PA to mTOR. Lastly, we found that the overexpression of DGKζ is sufficient to induce muscle fiber hypertrophy through an mTOR-dependent mechanism and this event requires DGKζ kinase activity (i.e. the synthesis of PA). Combined, these results indicate that DGKζ, but not PLD, plays an important role in mechanically-induced increases in [PA] and mTOR signaling. Furthermore, this study suggests that DGKζ could be a fundamental component of the mechanism(s) through which mechanical stimuli regulate skeletal muscle mass.
    Journal of Biological Chemistry 12/2013; 289(3). DOI:10.1074/jbc.M113.531392 · 4.57 Impact Factor
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    ABSTRACT: Chronic mechanical loading (CML) of skeletal muscle induces compensatory growth and the drug rapamycin has been reported to block this effect. Since rapamycin is considered to be a highly specific inhibitor of the mammalian target of rapamycin (mTOR), many have concluded that mTOR plays a key role in CML-induced growth regulatory events. However, rapamycin can exert mTOR-independent actions and systemic administration of rapamycin will inhibit mTOR signalling in all cells throughout the body. Thus, it is not clear if the growth inhibitory effects of rapamycin are actually due to the inhibition of mTOR signalling, and more specifically, the inhibition of mTOR signalling in skeletal muscle cells. To address this issue, transgenic mice with muscle specific expression of various rapamycin-resistant mutants of mTOR were employed. These mice enabled us to demonstrate that mTOR, within skeletal muscle cells, is the rapamycin-sensitive element that confers CML-induced hypertrophy, and mTOR kinase activity is necessary for this event. Surprisingly, CML also induced hyperplasia, but this occurred through a rapamycin-insensitive mechanism. Furthermore, CML was found to induce an increase in FoxO1 expression and PKB phosphorylation through a mechanism that was at least partially regulated by an mTOR kinase-dependent mechanism. Finally, CML stimulated ribosomal RNA accumulation and rapamycin partially inhibited this effect; however, the effect of rapamycin was exerted through a mechanism that was independent of mTOR in skeletal muscle cells. Overall, these results demonstrate that CML activates several growth regulatory events, but only a few (e.g. hypertrophy) are fully dependent on mTOR signalling within the skeletal muscle cells.
    The Journal of Physiology 09/2011; 589(Pt 22):5485-501. DOI:10.1113/jphysiol.2011.218255 · 5.04 Impact Factor
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    ABSTRACT: Non-technical summary Skeletal muscle comprises ∼40% of total body mass, and the control of muscle mass has significant effects on overall health. Skeletal muscle mass is determined by the balance of protein synthesis and degradation within muscle cells. We sought to determine which cellular proteins that control protein synthesis within muscle cells are associated with muscle growth after resistance exercise, a potent growth stimulus. We identified two proteins that were associated with muscle growth in humans: p70S6K and eIF2Bɛ. Follow up studies determined that eIF2Bɛ alone is sufficient to induce muscle growth. This is the first study to determine that this protein can induce skeletal muscle growth. These results further our understanding of how skeletal muscle responds to resistance exercise. Abstract The purpose of this study was to identify signalling components known to control mRNA translation initiation in skeletal muscle that are responsive to mechanical load and may be partly responsible for myofibre hypertrophy. To accomplish this, we first utilized a human cluster model in which skeletal muscle samples from subjects with widely divergent hypertrophic responses to resistance training were used for the identification of signalling proteins associated with the degree myofibre hypertrophy. We found that of 11 translational signalling molecules examined, the response of p(T421/S424)-p70S6K phosphorylation and total eukaryotic initiation factor 2Bɛ (eIF2Bɛ) protein abundance after a single bout of unaccustomed resistance exercise was associated with myofibre hypertrophy following 16 weeks of training. Follow up studies revealed that overexpression of eIF2Bɛ alone was sufficient to induce an 87% increase in cap-dependent translation in L6 myoblasts in vitro and 21% hypertrophy of myofibres in mouse skeletal muscle in vivo (P < 0.05). However, genetically altering p70S6K activity had no impact on eIF2Bɛ protein abundance in mouse skeletal muscle in vivo or multiple cell lines in vitro (P > 0.05), suggesting that the two phenomena were not directly related. These are the first data that mechanistically link eIF2Bɛ abundance to skeletal myofibre hypertrophy, and indicate that eIF2Bɛ abundance may at least partially underlie the widely divergent hypertrophic phenotypes in human skeletal muscle exposed to mechanical stimuli.
    The Journal of Physiology 06/2011; 589(Pt 12):3023-37. DOI:10.1113/jphysiol.2010.202432 · 5.04 Impact Factor
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    Medicine &amp Science in Sports &amp Exercise 09/2010; 42(10):7. DOI:10.1249/01.MSS.0000389388.95428.31 · 3.98 Impact Factor
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    ABSTRACT: It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.
    Molecular biology of the cell 09/2010; 21(18):3258-68. DOI:10.1091/mbc.E10-05-0454 · 4.47 Impact Factor

Publication Stats

158 Citations
23.10 Total Impact Points


  • 2010–2013
    • University of Wisconsin–Madison
      • Department of Comparative Biosciences
      Madison, Wisconsin, United States
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States