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Le Bris S. Quinn, Ph.D.
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The primary focus of Dr. Quinn’s research program is the cellular and molecular endocrinology of
skeletal muscle trophic factors. In normal human aging, skeletal muscle mass typically declines
by one-third between the ages of 50 and 80, a phenomenon termed “sarcopenia.” The consequences
of such age-related muscle atrophy are decreases in strength and endurance, leading to physical
frailty, including bone loss, loss of capacity for independent living, and greatly increased
tendency to fall (a leading cause of mortality in the elderly). A related age-associated problem
is the change in body composition; that is, decreasing lean:fat ratio, which is a major correlate
of insulin resistance. Both sarcopenia and age-associated changes in body composition may be
related to declines in growth hormone (GH) secretion, and hence in expression of the mediator of
GH effects, insulin-like growth factor-I (IGF-I). Hence, a large part of Dr. Quinn’s research
program is directed towards understanding and modifying the IGF-I signaling pathway in skeletal
muscle.
It has been known for some time that IGF-I, working through the type-1 IGF receptor, is a major
determinant of skeletal muscle hypertrophy in mammals. Surprisingly, however, the exact cellular
target of IGF-I action in skeletal muscle is still not clear. For a long time, researchers assumed
that IGF-I acted directly on muscle fibers to stimulate muscle protein synthesis. Recent work by
several groups (including Dr. Quinn’s) has instead shown that the major targets of IGF-I action are
skeletal muscle precursor cells known as satellite cells. It is now unclear whether IGF-I has any
satellite cell-independent actions on muscle fibers. To determine whether this occurs, Dr. Quinn’s
laboratory is performing a study in which the type-1 IGF receptor is overexpressed in cultured
muscle and in transgenic mice from a muscle fiber-specific promoter, which is not active in the
satellite cells. If IGF-I has satellite cell-independent actions, the muscle fiber-specific
overexpression of this nonsecreted protein should cause skeletal muscle hypertrophy independent of
stimulation of satellite cell proliferation and differentiation. Although this may appear to be
an academic point, this study has important implications for treatment of age-associated sarcopenia.
This study will determine whether exogenous manipulation of the IGF axis in skeletal muscle can
prevent sarcopenia without induction of satellite cell proliferation, thus minimizing the risks of
neoplasm and/or depletion of satellite cell reserve proliferative capacity.
A second major line of inquiry in Dr. Quinn’s laboratory is the regulation and mechanism of action
of a novel anabolic cytokine for skeletal muscle, interleukin-15 (IL-15). Dr. Quinn’s laboratory
has shown that IL-15 stimulates skeletal muscle fiber protein synthesis and inhibits protein
degradation by a mechanism, which is distinct from, and downstream of, that of IGF-I.
Additionally, Dr. Quinn’s work has shown that IL-15 inhibits fat deposition both in vivo
(in rats and mice) and in vitro (in adipogenic cell lines). In vitro, IL-15 decreases
expression of the adipogenic transcription factor PPAR gamma. Current work focuses on the
regulation of IL-15 and IL-15 receptor expression during aging, the mechanisms of action of IL-15
in skeletal muscle and fat, and the effects of IL-15 on insulin-stimulated glucose uptake by
skeletal muscle.
Dr. Quinn is Research Associate Professor, Division of Gerontology and Geriatric Medicine,
Department of Medicine. She currently serves on the National Scientific Advisory Council,
American Federation for Aging Research (AFAR).
Selected Relevant Publications
Damon SE, Haugk KL, Birnbaum RS, Quinn LS. Retrovirally-mediated overexpression of IGFBP-4:
Evidence that IGF is required for skeletal muscle differentiation. J Cell Physiol 175:109-120,
1998.
Kitzis V, Engrav LH, Quinn LS. Transient exposure to tumor necrosis-factor-alpha inhibits
collagen accumulation by cultured hypertrophic scar fibroblasts. J Surg Res 87:134-141, 1999.
Haugk KL, Wilson HMP, Swisshelm K, Quinn LS. IGF binding protein-related protein 1: An
autocrine/paracrine factor which inhibits skeletal myoblast differentiation but permits
proliferation in response to IGF. Endocrinol 141:100-110, 2000.
Carbó N, Lopez-Soriano J, Costelli P, Busquets S, Alvarez B, Baccino FM, Quinn LS, Lopez-Soriano FJ,
Argilés JM. Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Brit J Cancer
83:526-531, 2000.
Alvarez B, Quinn LS, Busquets S, Lopez-Soriano FJ, Argilés JM. Direct effects of tumor necrosis
factor alpha (TNF-a) on murine skeletal muscle. Bimodal effects on protein metabolism. Euro
Cytokine Netwk 12:399-410, 2001.
Alvarez B, Quinn LS, Busquets S, Lopez-Soriano FJ, Argilés JM. TNF-a modulates cytokine and
cytokine receptors in C2C12 myotubes. Cancer Lett 175:181-185, 2002.
Alvarez B, Quinn LS, Busquets S, Quiles MT, Lopez-Soriano FJ, Argilés JM. Tumor necrosis factor-
alpha exerts interleukin-6-dependent and –independent effects on cultured skeletal muscle cells.
Biochem Biophys Acta 1542:66-72, 2002. |
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