DONOVAN, C. M., and M. J. PAGLIASSOTTI. Quantitative assessment of pathways for lactate disposal in skeletal muscle fiber types. Med. Sci. Sports Exerc., Vol. 32, No. 4, pp. 772–777, 2000. Quantifying the contribution of the various skeletal muscle fiber types toward lactate disposal has proven elusive. In part, this can be attributed to the lack of adequate preparations for the study of all potential metabolic pathways involved. Toward this end our laboratory developed several perfused muscle preparations that are homogeneous for specific fiber types. This paper briefly reviews our findings regarding the influence of fiber type on lactate disposal in resting skeletal muscle and the metabolic pathways involved. Perfusing over a range of lactate concentrations, 1–12 mM, all fiber types were shown to switch from net production at low lactate concentrations to net consumption at higher concentrations. This transition occurred at lower lactate concentrations for Type I and IIa fibers, when compared with IIb fibers. For Type I and IIa fibers oxidation was observed to be the primary route of disposal accounting for approximately 50% of the lactate removed. For all fiber types, transamination was a significant pathway for the disposal of lactate carbon, whereas glyconeogenesis was the primary pathway for disposal in Type IIb fibers. The glyconeogenic capacity was quantitatively similar for Type IIa and IIb fibers but was negligible for Type I fibers. The pathway for glyconeogenesis in skeletal muscle was shown to be substantially different from that employed in hepatic glyconeogenesis. Results indicated that neither the TCA cycle nor phosphoenolpyruvate carboxykinase is involved in skeletal muscle glyconeogenesis. Our findings suggested that PEP formation in skeletal muscle glyconeogenesis occurs by “reversal” of the pyruvate kinase reaction.
The ability of skeletal muscle to remove lactate has been appreciated since the early work of Meyerhof et al. (25,26). Their work also elucidated metabolic pathways by which lactate disposal could occur. Interest in the contribution of various skeletal muscle fiber types toward these processes arose from several subsequent observations. That the various fiber types differ substantially in their oxidative capacity is now well documented (35). Specifically, homogenates from muscles composed predominantly of Type I and IIa fibers have been shown to have a greater capacity to oxidize lactate when compared with Type IIb muscle fibers (1). In vivo observations that 14C-lactate appears largely as 14CO2 during exercise and recovery has led to the proposal that disposal of lactate is largely a function of oxidative skeletal muscle fibers. A model of lactate exchange in which Type IIb fibers produce lactate, which is subsequently oxidized by Type I and IIa fibers has been proposed (6). Other investigators maintain that lactate formed during exercise is removed primarily through glyconeogenesis within skeletal muscle (13,15). This latter proposal implicates Type II muscle fibers as the primary site for disposal, as the capacity for de novo synthesis of glycogen appears proprietary to these fibers (23,31). Thus, the various skeletal muscle fiber types figure prominently in all current hypotheses regarding lactate disposal by skeletal muscle.
Attempts to quantify pathways of lactate disposal in various fiber types have relied extensively upon isotopic incorporation from 14C-lactate into other metabolites, e.g., glycogen, CO2, and alanine. Owing to the requisite small muscle mass and low rates of oxidation and glyconeogenesis, studies employing incubated mammalian skeletal muscle have relied almost exclusively upon such measures (4,7,22,40). However, the incorporation of label from 14C-lactate into other metabolites alone does not guarantee a measurement of net metabolic conversion (21). Net synthesis of the end product, consistent with the tracer incorporation, must also be observed (17,18,20). This latter requirement ensures that the observed tracer incorporation quantitatively reflects product synthesis, and not simply “nonproductive isotopic exchange” (21). Studies employing the perfused rat hindlimb have fared better in this respect, generally demonstrating net glycogen deposition and tracer incorporation (23,37). However, in assessing the contribution of various fiber types toward lactate disposal such studies are restricted to measurements of glyconeogenesis alone. This stems from the fact that other pathways of disposal, e.g., oxidation or transamination, are assessed from the circulation. In the perfused hindlimb, sampling from the circulation occurs in a major vessel representing the confluence of perfusate draining from many muscles and fiber types. Thus, the contribution of these pathways of disposal cannot be determined for specific fiber types. Further compromising estimates from perfused rat hindlimb preparations are disparities in blood flow to the various muscles (11).