Abstract. It has been suggested that intramyocellular lipids
(IMCLs) may serve as biomarkers of insulin resistance and
mitochondrial dysfunction. Using a hind-limb mouse model of
burn trauma, we tested the hypothesis that severe localized
burn trauma involving 5% of the total body surface area causes
a local increase in IMCLs in the leg skeletal muscle. We
quantified IMCLs from ex vivo intact tissue specimens using
High-Resolution Magic Angle Spinning (HRMAS) 1H NMR
and characterized the accompanying gene expression patterns
in burned versus control skeletal muscle specimens. We also
quantified plasma-free fatty acids (FFAs) in burn versus
control mice. Our results from HRMAS 1H NMR measure-
ments indicated that IMCL levels were significantly increased
in mice exposed to burn trauma. Furthermore, plasma FFA
levels were also significantly increased, and gene expression
of Glut4, insulin receptor substrate 1 (IRS1), glycolytic genes,
and PGC-1ß was downregulated in these mice. Backward
stepwise multiple linear regression analysis demonstrated that
IMCL levels correlated significantly with FFA levels, which
were a significant predictor of IRS1 and PGC-1ß gene
expression. We conclude from these findings that IMCLs can
serve as metabolic biomarkers in burn trauma and that FFAs
and IMCLs may signal altered metabolic gene expression.
This signaling may result in the observed burn-induced insulin
resistance and skeletal muscle mitochondrial dysfunction.
We believe that IMCLs may therefore be useful biomarkers
in predicting the therapeutic effectiveness of hypolipidemic
agents for patients with severe burns.
Severe burns carry high rates of mortality and morbidity
(1,2), and are complicated by the associated development of
insulin resistance (3,4) and mitochondrial dysfunction (5).
Treatment of patients suffering from burn trauma can also be
complicated by organ dysfunction and the late development
of infection (1,2). For these reasons, the pathophysiology of
burn trauma remains an area of intense study (2). It is believed
that early administration of appropriate therapeutic factors
may be useful in limiting post-burn metabolic dysfunction. In
order to evaluate the effectiveness of such factors, metabolic
biomarkers are required.
In addition to its association with burn trauma, insulin
resistance is also frequently observed in various metabolic
diseases, including obesity, dyslipidemia, arterial hyper-
tension, and type 2 diabetes. Skeletal muscle wasting in
insulin-resistant burn patients has been documented and
develops due to a lack of anabolic effects, as well as enhanced
gluconeogenesis and protein catabolism (6,7) in the burned
skeletal tissue. Although the molecular mechanisms under-
lying abnormal insulin function in burn victims have not
been elucidated, there is increasing evidence that plasma-free
fatty acids (FFAs) may play a role in inducing insulin
resistance (8). Because fatty acid metabolism and glucose
levels are closely linked, aberrations in FFA levels, such as
through accumulation of lipids or triglycerides in the muscle,
may lead to insulin resistance (9).
Aberrations in the peroxisome proliferator-activated
receptor coactivator 1 (PPARγ coactivator-1 or PGC-1)
family of coactivators (10,11) are also related to metabolic
abnormalities. PGC-1α and PGC-1ß are close homologs and
share extensive sequence identity (12). In general, PGC-1
coactivators play a critical role in the maintenance of
glucose, lipid and energy homeostasis, and are likely to be
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 21: 825-832, 2008
Murine intramyocellular lipids quantified by NMR
act as metabolic biomarkers in burn trauma
A. ARIA TZIKA1,2,4, LOUKAS G. ASTRAKAS1,2, HAIHUI CAO1,2, DIONYSSIOS MINTZOPOULOS1,2,4,
QUNHAO ZHANG1,4, KATIE PADFIELD1,4, HONGUE YU1,2, MICHAEL N. MINDRINOS3,
LAURENCE G. RAHME4and RONALD G. TOMPKINS4
1NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burn Institute,
Harvard Medical School, Boston, MA 02114; 2Athinoula A. Martinos Center of Biomedical Imaging,
Department of Radiology, Massachusetts General Hospital, Boston, MA 02114; 3Department of Biochemistry,
Stanford University School of Medicine, Stanford, CA 94305; 4Department of Surgery, Massachusetts General
Hospital and Shriners Burn Institute, Harvard Medical School, Boston, MA 02114, USA
Received February 1, 2008; Accepted March 17, 2008
Correspondence to: Dr A. Aria Tzika, NMR Surgical Laboratory,
Department of Surgery, Massachusetts General Hospital, Harvard
Medical School, Room 261, 51 Blossom Street, Boston, MA 02114,
Key words: nuclear magnetic resonance, skeletal muscle, burn
trauma, lipids, PGC-1ß, mitochondria, metabolism, biomarkers
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TZIKA et al: INTRAMYOCELLULAR LIPIDS AS METABOLIC BIOMARKERS IN BURNS