Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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Several studies have demonstrated the effect of exercise on substrate utilization

in normal, obese and diabetic myocardium. In diet-induced obese rats, exercise

increased insulin-stimulated phosphorylation of insulin receptor (IR), protein kinase

B (PKB/Akt) and insulin receptor substrates (IRS-1 & -2) [ 30 , 31 ]. However, the

effect of exercise on myocardial substrate utilization has not been investigated in

these studies [ 20 ]. Streptozotocin (STZ)-induced type 1 diabetic rats exposed to

exercise training showed unaltered oxidation rate of FAs in the myocardium [ 32 ],

despite the increased rates of glucose oxidation and glycolysis [ 12 ]. In agreement

with these findings, Hafstad et al. [ 33 ] reported increased myocardial glucose oxi-

dation with no changes in the rate of FAs oxidation after treadmill running in diet-

induced insulin-resistant mice. On the contrary, treadmill running didn’t affect

glucose oxidation and glycolysis in the normal myocardium [ 12 ]. Another study

conducted by Burelle et al. [ 34 ] demonstrated an increase in the oxidation rate of

glucose and FAs and a decrease in glycolysis in the heart of normal rats subjected to

treadmill running.

Studies on the effect of exercise on metabolism in other organs show diverging

findings. Katsumura et al. [ 35 ] reported no influence of exercise on the expression

of lipid metabolism-related enzymes mRNA in the liver, epididymal adipose tissue

and gastrocnemius muscle of high-fat diet-fed mice. High-altitude deer mice accli-

matized to hypoxia showed increased muscular capacity for the uptake and oxida-

tion of circulatory glucose during exercise [ 36 ]. In the brain of aged rats, exercise

improved mitochondrial function without increasing mitochondrial biogenesis [ 37 ].

As a response to exercise, skeletal muscles showed increased expression of genes

involved in mitochondrial biogenesis, oxidative phosphorylation and FA oxidation

through inducing the transcription factor EB [ 38 ].

3 Exercise Attenuates Myocardial Lipotoxicity

Free fatty acids (FFAs), the primary energy substrate utilized by the cardiac cells,

are supplied via lipolysis of triacylglycerols (TAG) or from blood [ 39 ]. The diabetic

heart is known to have changes in both glucose and FFAs availability [ 29 ]. In diabe-

tes, the intracellular accumulation of TAG and non-esterified fatty acids (NEFA)

contributes to apoptosis and build-up of toxic intermediates which result in lipotox-

icity. These harmful effects can impair the cardiac function and remodeling in the

diabetic myocardium [ 40 , 41 ].

In type 2 diabetic patients, cardiac dysfunction has been associated with intra-

myocardial TAG accumulation [ 42 ]. In addition, accumulation of TAG and shunting

of fatty acids into non-oxidative pathways can trigger accumulation of ceramide and

diacylglycerol (DAG). At high concentrations, these intermediates may disrupt

insulin signaling [ 43 ], induce apoptosis [ 44 ] and increase fibrosis of cardiomyo-

cytes through activation of protein kinases (PKCβ) [ 45 ].

In normal mice, short-term intensive swim training reduced cardiac levels of

ceramide and DAG, and up-regulated diacylglycerol transferase 1 (DGAT1) (TAG

12 Exercise Amaliorates Metabolic Disturbances and Oxidative Stress in Diabetic...