Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism

Abstract

Skeletal muscle contains two populations of mitochondria that appear to be differentially affected by disease and exercise training. It remains unclear how these mitochondrial subpopulations contribute to fiber type-related and/or training-induced changes in fatty acid oxidation and regulation of carnitine palmitoyltransferase-1beta (CPT1beta), the enzyme that controls mitochondrial fatty acid uptake in skeletal muscle. To this end, we found that fatty acid oxidation rates were 8.9-fold higher in subsarcolemmal mitochondria (SS) and 5.3-fold higher in intermyofibrillar mitochondria (IMF) that were isolated from red gastrocnemius (RG) compared with white gastrocnemius (WG) muscle, respectively. Malonyl-CoA (10 muM), a potent inhibitor of CPT1beta, completely abolished fatty acid oxidation in SS and IMF mitochondria from WG, whereas oxidation rates in the corresponding fractions from RG were inhibited only 89% and 60%, respectively. Endurance training also elicited mitochondrial adaptations that resulted in enhanced fatty acid oxidation capacity. Ten weeks of treadmill running differentially increased palmitate oxidation rates 100% and 46% in SS and IMF mitochondria, respectively. In SS mitochondria, elevated fatty acid oxidation rates were accompanied by a 48% increase in citrate synthase activity but no change in CPT1 activity. Nonlinear regression analyses of mitochondrial fatty acid oxidation rates in the presence of 0-100 muM malonyl-CoA indicated that IC(50) values were neither dependent on mitochondrial subpopulation nor affected by exercise training. However, in IMF mitochondria, training reduced the Hill coefficient (P < 0.05), suggesting altered CPT1beta kinetics. These results demonstrate that endurance exercise provokes subpopulation-specific changes in mitochondrial function that are characterized by enhanced fatty acid oxidation and modified CPT1beta-malonyl-CoA dynamics.

Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

“…However, selectively greater increases in palmitate oxidation in SS mitochondria (ϩ100%) compared with IMF mitochondria (ϩ46%) have been observed previously in muscles of endurance trained rats (66), in which PGC-1␣ was undoubtedly also increased. All other reports (12)(13)(14), except one (15), have found that the mRNA abundance of skeletal muscle CPTI, whose protein product is a key regulator of fatty acid oxidation, was not altered by PGC-1␣ overexpression.…”

“…In one study from our laboratory (69) and in several others by Muoio and co-workers (2,66,70), the rates of fatty acid oxidation have been shown to be greater in mitochondria obtained from red muscle than in mitochondria obtained from white muscle. These studies suggest that there are intrinsic differences in the capacities to oxidize fatty acids by red and white muscle mitochondria.…”

“…Because previous reports have shown that SS mitochondria exhibit greater metabolic plasticity than IMF mitochondria (16,17,66), we examined proteins in SS and IMF mitochondria. In agreement with previous studies showing that PGC-1␣ induced the expression of COXIV and mTFA in C 2 C 12 skeletal muscle cells (44,65), PGC-1␣ also induced the expression of COXIV and mTFA proteins in skeletal muscle SS and IMF mitochondria.…”

Exercise-induced attenuation of obesity, hyperinsulinemia, and skeletal muscle lipid peroxidation in the OLETF rat

“…Activation of PPAR␦ (38) and overexpression of PGC-1␣ (36) upregulate fatty acid oxidation. Endurance-type training has also been shown to increase fatty acid oxidation in the vastus lateralis muscle of obese women (13) and in red and white gastrocnemius muscle of rats run on a treadmill for 10 wk (30). Additional studies demonstrate that the capacity to oxidize palmitate in skeletal muscle is significantly reduced with human obesity and negatively associated with body mass index (28).…”

Evaluation of Mitochondrial Functions and Dysfunctions in Muscle Biopsy Samples

“…Mitochondria are located either around the nuclei, this subgroup is called subsarcolemmal mitochondria, or nestled between myofibrils. These mitochondria are named intermyofibrillar and have distinct activity from subsarcolemmal ones (Koves et al, 2005;Mollica et al, 2006). Intermyofibrillar mitochondria are mainly dedicated to energy production for muscle fiber contraction.…”