In this review, the present knowledge about the mechanisms involved in the control of the phenotypic expression of mammalian muscle fibers is summarized. There is a discussion as to how the activity imposed on the muscle fibers by the motoneuron finally induces in the muscle cells the expression of those genes that define its particular phenotype. The functional and molecular heterogeneity of skeletal muscle is thus defined by the existence of motor units with varied function, while the homogeneity of muscle fibers belonging to the same motor unit is yet another indication of the importance of activity in the control of gene expression of the mammalian muscle fiber.

Neural control of phenotypic expression in mammalian muscle fibers.

Mammalian skeletal muscle is an extremely heterogeneous tissue, composed of a large variety of fiber types. These fibers, however, are not fixed units but represent highly versatile entities capable of responding to altered functional demands and a variety of signals by changing their phenotypic profiles. This adaptive responsiveness is the basis of fiber type transitions. The fiber population of a given muscle is in a dynamic state, constantly adjusting to the current conditions. The full range of adaptive ability spans fast to slow characteristics. However, it is now clear that fiber type transitions do not proceed in immediate jumps from one extreme to the other, but occur in a graded and orderly sequential manner. At the molecular level, the best examples of these stepwise transitions are myofibrillar protein isoform exchanges. For the myosin heavy chain, this entails a sequence going from the fastest (MHCIIb) to the slowest (MHCI) isoform, and vice-versa. Depending on the basal protein isoform profile and hence the position within the fast-slow spectrum, the adaptive ranges of different fibers vary. A simple transition scheme has emerged from the multitude of data collected on fiber type conversions under a variety of conditions.

Mammalian skeletal muscle fiber type transitions

Metabolic differentiation of muscle tissue may be understood from the viewpoints of quantitative and qualitative adaptation. Quantitatively, it is the consequence of a balance of input of chemical energy and output of mechanical work in the myofibrillar apparatus. Qualitatively, it is the expression of an adjustment to the functional characteristics of the muscle, such as the quality and temporal pattern of energy expenditure (e.g. steady and continuous, steady and discontinuous or dicontinuous performance of work. The kinds of metabolic differentiation possible are based on the fact that muscle cells may draw energy from the oxidation of various fuels. The caloric values of the various fuels determine their different theoretical maximum energy-yields. The nature of the fuel also determines the type of its metabolism, especially with regard to an obligatory or nonobligatory aerobic catabolism. Energy-output in cell metabolism depends finally on the catabolic rate. Nature of the fuel, type of metabolism and catabolic rate thus represent fundamental elements in metabolic differentiation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1969.tb00674.x

Metabolic Differentiation of Distinct Muscle Types at the Level of Enzymatic Organization

Intermittant long-term stimulation of fast rabbit muscles up to 28 days with a frequency pattern resembling that of a slow muscle (10 Imp/sec) led to a slowing of the time course of contraction already during the first week. There was an increase of tetanic tension as well. The observed rearrangement of activities of key enzymes of energy supplying metabolism was found to occur sequentially. Decreases of extramitochondrial enzymes of glycogenolysis (phosphorylase), glycolysis (triosephosphate dehydrogenase, lactate dehydrogenase) and energy rich phosphate transfer were found initially together with a decrease of mitochondrial glycerolphosphate dehydrogenase. The isozyme pattern of lactate dehydrogenase was changed. Large initial increases were found in enzymes involved in glucose phosphorylation (hexokinase) and fatty acid activation (palmitoyl-CoA synthetase). Later an increase of key enzymes of the citric acid cycle (citrate synthase) and fatty acid oxidation (3-hydroxyacyl-CoA dehydrogenase) as well as ketone body utilization (3-ketoacid-CoA transferase) could be shown. Histochemical staining and comparative activity determination of succinate dehydrogenase in single fibres revealed that the mosaic like fibre composition of the fast muscle was transformed into a more uniform population resembling that of a predominantly slow muscle.

Effects of long-term electrical stimulation on some contractile and metabolic characteristics of fast rabbit muscles.

ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates.

Cross-innervations and re-innervations were performed on the slow (“red”) m. soleus and the fast (“white”) m. extensor digitorum of the rabbit. Innervation of the slow soleus muscle with “fast” motor neurons causes a significant change of the metabolic type of the muscle. This transformation consists in a parallel increase of the activity levels of glycogen phosphorylase, of all the investigated glycolytic enzymes (phosphofructokinase, triosephosphate isomerase, triosephosphate dehydrogenase, phosphoglycerate kinase, glycerate phosphomutase, phosphopyruvate hydratase, lactate dehydrogenase), of adenylate kinase and mitochondrial glycerolphosphate dehydrogenase. A concomitant and parallel decrease is found in the activity levels of extramitochondrial hexokinase, and alanine aminotransferase, of all the investigated enzymes of the citric acid cycle (intramitochondrial citrate synthase, and succinate dehydrogenase, extra- and intramitochondrial malate dehydrogenase, and NADP isocitrate dehydrogenase), of intramitochondrial 3-hydroxyacyl-CoA dehydrogenase and glutamate dehydrogenase, and of extra- and intramitrochondrial aspartate aminotransferase. In spite of the marked changes in absolute activities, no alterations occur with regard to the ratios of enzymes and enzyme groups which by comparison of functionally different muscles have been classified as constant. Changes in the activity ratios concern the same enzymes which in previous studies have been shown to be characteristic of the metabolic type (phosphorylase/hexokinase, triosephosphate dehydrogenase/citrate synthase, lactate dehydrogenase/citrate synthase, triosephosphate dehydrogenase/3-hydroxyacyl-CoA dehydrogenase, adenylate kinase/creatine kinase). The alterations show that a conversion of the metabolic type from “slow” to “fast” takes place and indicate a specific influence of the innervation on metabolic differentiation in muscle, that is the control of a specific pattern of enzyme synthesis. Due to the obvious failure of innervation of the fast extensor muscle with “slow” motor neurons from the tibial nerve, no significant changes were observed in this muscle.

Günter Golisch

Papers

Metabolic differentiation of rabbit skeletal muscle as induced by specific innervation.