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PubMed1999

Incorporation and utilization of [3-13C]lactate and [1,2-13C]acetate by rat skeletal muscle.

Skeletal muscle can utilize many different substrates, and traditional methodologies allow only indirect discrimination between oxidative and nonoxidative uptake of substrate, possibly with contamination by metabolism of other internal organs. Our goal was to apply 1H- and 13C-nuclear magnetic resonance spectroscopy to monitor the patterns of [3-13C]lactate and [1,2-13C]acetate (model of simple carbohydrates and fats, respectively) utilization in resting vs. contracting muscle extracts of the isolated perfused rat hindquarter. Total metabolite concentrations were measured by using NADH-linked fluorometric assays. Fractional oxidation of [3-13C]lactate was unchanged by contraction despite vascular endogenous lactate accumulation. Although label accumulated in several citric acid cycle (CAC) intermediates, contraction did not increase the concentration of CAC intermediates in any muscle extracts. We conclude that 1) the isolated rat hindquarter is a viable, well-controlled model for measuring skeletal muscle 13C-labeled substrate utilization; 2) lactate is readily oxidized even during contractile activity; 3) entry and exit from the CAC, via oxidative and nonoxidative pathways, is a component of normal muscle metabolism and function; and 4) there are possible differences between gastrocnemius and soleus muscles in utilization of nonoxidative pathways.

Acetates↗

PubMed1998

Influence of acclimation temperature on mitochondrial DNA, RNA, and enzymes in skeletal muscle.

Skeletal muscle fibers typically undergo modifications in their mitochondrial content, concomitant with alterations in oxidative metabolism that occur during the development of muscle fiber and in response to physiological stimuli. We examined how cold acclimation affects the mitochondrial properties of two fish skeletal muscle fiber types and how the regulators of mitochondrial content differed between tissues. After 2 mo of acclimation to either 4 or 18 degrees C, mitochondrial enzyme activities in both red and white muscle were higher in cold-acclimated fish. No significant differences were detected between acclimation temperatures in the abundance of steady-state mitochondrial mRNA (cytochrome-c oxidase 1, subunit 6 of F0F1-ATPase), rRNA (16S), or DNA copy number. Steady-state mRNA for nuclear-encoded respiratory (adenine nucleotide translocase 1) and glycolytic genes showed high interindividual variability, particularly in the cold-acclimated fish. Although mitochondrial enzymes were 10-fold different between the two muscle types, mitochondrial DNA copy number differed only 4-fold. The relative abundance of mitochondrial mRNA and nuclear mRNA in red and white muscle reflected the differences in copy number of their respective genes. These data suggest that the response to physiological stimuli and determination of tissue-specific mitochondrial properties likely result from the regulation of nuclear-encoded genes.

Acclimatization↗

PubMed2002

Related expression of MyoD and Myf5 with myosin heavy chain isoform types in bovine adult skeletal muscles.

Skeletal muscles are characterized as fast and slow muscles, according to the expression pattern of myosin heavy chain (MyHC) isoforms in the muscle fibers. To investigate the relationships between MyHC isoforms and myogenic regulatory factors (MRFs) including MyoD, Myf5, myogenin, and MRF4 in adult skeletal muscles, expressions of these MRFs in the ten muscles of three cows were analyzed by a semi-quantitative RT-PCR. The results showed that MyoD expression was significantly lower in the lingual muscles (TN), masseter (MS) and diaphragm (DP), which lack MyHC-2x (fast glycolytic) expression and abound with MyHC-slow (slow oxidative) and/or MyHC-2a (fast oxidative), than it was in the pectoralis (PP), psoas major (PM), longissimus thoracis (LT), spinnalis (SP), semitendinosus (ST), semimembranosus (SM), and biceps femoris (BF). In contrast, the Myf5 expression in TN, MS, and DP was significantly higher than in PM, LT, ST, SM, and BF. No significant difference was observed in myogenin and MRF4 expression among the muscles tested. The results suggest that MyoD and Myf5 influence the MyHC isoform expression, although the effects are not decisive in specifying the phenotypes of adult muscles.

Aging↗

PubMed2001

Structural and functional changes in the microvasculature of disused skeletal muscle.

Skeletal muscle and its microvasculature can exhibit remarkable plasticity in response to decreased functional demand (i.e., muscle disuse). Since the microvascular adaptation to disuse does seem to not depend solely on reduced demand, this review examines the various factors that may be responsible for the observed regression of microvascular structure and function during disuse. There are several animal models of muscle disuse; their common feature is that they are associated with a variety of confounding effects that make the interpretation of the "pure" disuse effect challenging. As well, in clinical studies, the effect of disuse can be difficult to separate from that of various pathologies. Regardless of methodological difficulties, degeneration of the capillary wall, capillary loss, arteriolar remodelling, reduced resting state blood flow, and reduced arteriolar responsiveness to acute vasodilative and vasoconstrictive stimuli have all been observed in disused muscles. The level, and presence/absence of these changes may depend on many factors including the duration of disuse, degree of muscle atrophy, residual muscle activity, microvascular blood flow, release of vasoactive agents from the degenerating muscle, muscle type, and the particular pathology associated with the muscle withering in humans. It is the present challenge to discover the presence/absence of key agents (possibly originating at the interface between the blood stream and the vascular wall, within the extracellular matrix, or the muscle fibres themselves) that alter the intra- and/or inter-cellular signalling to explain the mechanism of adaptation of the microvasculature to skeletal muscle disuse.

Animals↗

PubMed2002

Duality of G protein-coupled mechanisms for beta-adrenergic activation of NKCC activity in skeletal muscle.

Skeletal muscle Na(+)-K(+)-2Cl(-) cotransporter (NKCC) activity provides a potential mechanism for regulated K(+) uptake. beta-Adrenergic receptor (beta-AR) activation stimulates skeletal muscle NKCC activity in a MAPK pathway-dependent manner. We examined potential G protein-coupled pathways for beta-AR-stimulated NKCC activity. Inhibition of G(s)-coupled PKA blocked isoproterenol-stimulated NKCC activity in both the slow-twitch soleus muscle and the fast-twitch plantaris muscle. However, the PKA-activating agents cholera toxin, forskolin, and 8-bromo-cAMP (8-BrcAMP) were not sufficient to activate NKCC in the plantaris and partially stimulated NKCC activity in the soleus. Isoproterenol-stimulated NKCC activity in the soleus was abolished by pretreatment with pertussis toxin (PTX), indicating a G(i)-coupled mechanism. PTX did not affect the 8-BrcAMP-stimulated NKCC activity. PTX treatment also precluded the isoproterenol-mediated ERK1/2 MAPK phosphorylation in the soleus, consistent with NKCC's MAPK dependency. Inhibition of isoproterenol-stimulated ERK activity by PTX treatment was associated with an increase in Akt activation and phosphorylation of Raf-1 on the inhibitory residue Ser(259). These results demonstrate a novel, muscle phenotype-dependent mechanism for beta-AR-mediated NKCC activation that involves both G(s) and G(i) protein-coupled mechanisms.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2006

Functional heterogeneity of side population cells in skeletal muscle.

Skeletal muscle regeneration has been exclusively attributed to myogenic precursors, satellite cells. A stem cell-rich fraction referred to as side population (SP) cells also resides in skeletal muscle, but its roles in muscle regeneration remain unclear. We found that muscle SP cells could be subdivided into three sub-fractions using CD31 and CD45 markers. The majority of SP cells in normal non-regenerating muscle expressed CD31 and had endothelial characteristics. However, CD31(-)CD45(-) SP cells, which are a minor subpopulation in normal muscle, actively proliferated upon muscle injury and expressed not only several regulatory genes for muscle regeneration but also some mesenchymal lineage markers. CD31(-)CD45(-) SP cells showed the greatest myogenic potential among three SP sub-fractions, but indeed revealed mesenchymal potentials in vitro. These SP cells preferentially differentiated into myofibers after intramuscular transplantation in vivo. Our results revealed the heterogeneity of muscle SP cells and suggest that CD31(-)CD45(-) SP cells participate in muscle regeneration.

Animals↗

PubMed2000

Stress proteins of 70 kDa in chronically exercised skeletal muscle.

Skeletal muscle fibres of untrained animals experience a stress response following exercise. This study was aimed at investigating whether chronic exercise modulates stress proteins of 70 kDa (HSP70s) in skeletal muscle. In the soleus muscle of Wistar rats, adherence to an incremental programme of treadmill running (IPTR) of 3 months duration up-regulated the levels of the beta-subunit of the mitochondrial F1-ATPase and those of HSP72, GRP75 and GRP78. Neither beta-F1-ATPase nor sarcoplasmic reticulum Ca2+-ATPase levels changed with training in the extensor digitorum longus (EDL) muscle. However, HSP70s increased during training. In soleus muscle slices of animals sacrificed 3 days after completing the IPTR, HSP72 and GRP75 were synthesized at lower rates than in sedentary animals while the GRP78 synthesis rate increased. Trained, rested animals also experienced a stress response following acute exercise of lower intensity than that of the actual training sessions. The data suggest that up-regulation of HSP70s by chronic exercise depends upon continued physical activity. Furthermore, the inverse correlation between levels and rates of synthesis of HSP72 during rest periods suggests the operation of a feedback regulatory loop aimed at reestablishing the threshold levels characteristic of unstressed fibres.

Animals↗

PubMed2001

Current aspects of lactate exchange: lactate/H+ transport in human skeletal muscle.

Skeletal muscle is capable of producing and releasing large amounts of lactate and at the same time taking up lactate and using it as a respiratory fuel. The release and uptake of lactate both involve transmembrane transport, which is mediated mainly by a membrane protein called the monocarboxylate transporter (MCT). MCTs mediate membrane transport with an obligatory 1:1 coupling between lactate and H+ fluxes, and is therefore of great importance for pH regulation, especially during intense muscle activity. The total lactate and H+ transport capacity is higher in membranes from oxidative fibers than in membranes from more glycolytic fibers. There are two isoforms of MCT present in skeletal muscle, MCT1 and MCT4. In human muscle samples, there is a positive correlation between the proportion of type I fibers and MCT1 density. In contrast, the MCT4 density in human muscle is independent of fiber type and displays a large interindividual variation. Although the two isoforms have identical transport kinetics (Km), they may have different roles in muscle. MCT1 and MCT4 respond differently to a high-intensity training session, which suggests that these two isoforms are regulated differently.

Biological Transport↗

PubMed1997

The functional and morphological damage of ischemic reperfused skeletal muscle.

Skeletal muscle is frequently damaged by ischemia-reperfusion both caused by direct injury and also by surgery. The purpose of the present experiments was to examine how the different types of skeletal muscles (fast and slow) react functionally and morphologically after 1 and 2 h of ischemia followed by different periods of reperfusion. The fast-twitch (musculus extensor digitorum longus, EDL) and the slow-twitch (musculus soleus, SOL) muscle of Wistar rats were prepared. They were stimulated in vivo, either directly or indirectly at different reperfusion times following tourniquet ischemia, and the contraction force of the muscles was recorded. The morphological changes were examined by light microscopy. At early reperfusion times, the contraction force of the EDL muscle was reduced by 40 and 90% after 1 and 2 h of ischemia, respectively. The contraction force was about 50% at the end of a 2-week reperfusion period in the 1-hour ischemia group and it increased significantly (from 5 to 38%) during the second week if the ischemia lasted for 2 h. Reduction of contraction force in the SOL muscle was over 50 and 90% following 1 and 2 h of ischemia, respectively, and it started to improve from the 2nd week. Morphological changes of the two types of muscle were identical. At early reperfusion times granulocytes were seen in the blood vessels adhering to the endothelium. 24 h later neutrophil granulocytes migrated into the endomysium and thereafter into the perimysium. One week after 1 h of ischemia both muscles showed normal histology. However, the structural regeneration process only started at the end of the 1st week of reperfusion after 2 h of the ischemic damage. The following conclusions can be drawn. (1) There is functional morphological evidence of ischemic and reperfusion injury in both muscles after 24 h and also after 1 week of reperfusion. (2) Functionally, the two types of muscles regenerate differently, i.e. the SOL starts to regenerate earlier than the EDL. (3) Morphologically the two types of muscle show the same reactions. An increase in the time of ischemia from 1 to 2 h delays the regeneration processes.

Animals↗

PubMed2004

Vasodilatory mechanisms in contracting skeletal muscle.

Skeletal muscle blood flow is closely coupled to metabolic demand, and its regulation is believed to be mainly the result of the interplay of neural vasoconstrictor activity and locally derived vasoactive substances. Muscle blood flow is increased within the first second after a single contraction and stabilizes within approximately 30 s during dynamic exercise under normal conditions. Vasodilator substances may be released from contracting skeletal muscle, vascular endothelium, or red blood cells. The importance of specific vasodilators is likely to vary over the time course of flow, from the initial rapid rise to the sustained elevation during steady-state exercise. Exercise hyperemia is therefore thought to be the result of an integrated response of more than one vasodilator mechanism. To date, the identity of vasoactive substances involved in the regulation of exercise hyperemia remains uncertain. Numerous vasodilators such as adenosine, ATP, potassium, hypoxia, hydrogen ion, nitric oxide, prostanoids, and endothelium-derived hyperpolarizing factor have been proposed to be of importance; however, there is little support for any single vasodilator being essential for exercise hyperemia. Because elevated blood flow cannot be explained by the failure of any single vasodilator, a consensus is beginning to emerge for redundancy among vasodilators, where one vasoactive compound may take over when the formation of another is compromised. Conducted vasodilation or flow-mediated vasodilation may explain dilation in vessels (i.e., feed arteries) not directly exposed to vasodilator substances in the interstitium. Future investigations should focus on identifying novel vasodilators and the interaction between vasodilators by simultaneous inhibition of multiple vasodilator pathways.

Animals↗

PubMed2001

Systemic administration of naked DNA: gene transfer to skeletal muscle.

Skeletal muscle is a promising target tissue for the gene therapy of both muscle and non-muscle disorders. Gene transfer into muscle tissue can produce a variety of physiologically active proteins and may ultimately be applied to the treatment of many diseases. A variety of methods have been studied to transfer genes into skeletal muscle, including viral and non-viral vectors. In this review, we discuss recent developments in the non-viral delivery of genes to muscles.

Animals↗

PubMed1999

Diffuse metastatic infiltration of a carcinoma into skeletal muscle.

Skeletal muscle is one of the most unusual sites of metastasis from any malignancy. We report a patient with rapidly progressive contractures due to metastatic infiltration of a carcinoma of unknown origin into the skeletal muscle. This 61-year-old man presented with a 1-month history of rapidly evolving, painful restriction of mobility of his right arm and his legs. Computed tomography showed diffuse metastatic nodules in all muscles, particularly in the hip abductors. Muscle biopsy revealed extensive infiltration of the muscle with carcinoma cells.

Biopsy↗

PubMed2002

Cells that participate in regeneration of skeletal muscle.

Skeletal muscle is a post-mitotic tissue that is thought, conventionally to be maintained by repair and regeneration by a population of stem cell-like satellite cells. Recent findings have brought into question the extent to which these satellite cells represent a single homogeneous population and whether they are the only source of myogenic cells in mature muscle. It has been shown that myogenic cells can be derived from the bone marrow or from the supposedly post-mitotic nuclei of muscle fibres. However, neither of these sources has been demonstrated to generate more than a tiny proportion of muscle nuclei. It remains possible nonetheless that such mechanisms might be exploited for therapeutic uses in primary muscle disease.

Cell Differentiation↗

PubMed2006

Ca2+ activation of diffusible and bound pools of mu-calpain in rat skeletal muscle.

Skeletal muscle fibres contain ubiquitous and muscle-specific calcium-dependent proteases known as calpains. During normal activity, intracellular [Ca(2+)] in muscle fibres increases to high levels ( approximately 2-20 microm), and it is not apparent how this can be reconciled with the activation properties of the calpains. Calpains evidently do not cause widespread proteolytic damage within muscle fibres under normal circumstances, but do have a role in necrosis in dystrophic muscle fibres. In this study, we examined the in situ localization and regulation of calpains in muscle fibres in order to identify how they are attuned to normal function. The sarcolemma of individual muscle fibres of the rat was removed by microdissection (fibre 'skinning') in order to determine the compartmentalization and diffusibility of the two most Ca(2+)-sensitive calpains, mu-calpain and calpain-3, and to permit precise manipulation of cytoplasmic [Ca(2+)] under physiological in situ conditions. Passive force production in stretched fibres, which indicates the patency of the important elastic structural protein titin, was used as a sensitive assay of the amount of diffusible proteolytic activity in individual fibre segments and in muscle homogenates at set [Ca(2+)]. All calpain-3 is bound tightly within a fibre, whereas most mu-calpain ( approximately 0.2 microm) is initially freely diffusible in the cytoplasm at resting [Ca(2+)] but binds within seconds at high [Ca(2+)]. [Ca(2+)] has to be raised to >/= 2 microm for >/= 1 min to initiate detectable autolysis of mu-calpain and to activate appreciable proteolytic activity. If the [Ca(2+)] is raised sufficiently for long enough to initiate substantial autolysis of mu-calpain, the Ca(2+) sensitivity of the proteolytic activity is greatly increased, and it remains active even at 300 nm Ca(2+), with activity only ceasing if the [Ca(2+)] is decreased to approximately 50 nm Ca(2+), close to the normal resting [Ca(2+)]. These findings on the Ca(2+)- and time-dependent binding, autolytic and proteolytic properties of mu-calpain under physiological conditions demonstrate how it is precisely attuned to avoid uncontrolled proteolytic activity under normal circumstances, and indicate why it could lead to substantial proteolytic damage if resting or localized [Ca(2+)] is elevated, as is likely to occur after eccentric contraction and in dystrophic muscle.

Animals↗

PubMed2002

Early changes of type 2B fibers after denervation of rat EDL skeletal muscle.

Skeletal muscle type 2B fibers normally receive a moderate level of motoneuron discharge. As a consequence, we hypothesize that type 2B fiber properties should be less sensitive to the absence of the nerve. Therefore, we have investigated the response of sarcoplasmic reticulum and myofibrillar proteins of type 2B fibers isolated from rat extensor digitorum longus muscle after denervation (2 and 7 days). Single fibers were identified by SDS-PAGE of myosin heavy chain isoforms. Electrophysiological and isometric contractile properties of the whole muscle were also analyzed. The pCa-tension relationship of type 2B single fibers was shifted to the left at 2 days and to right at 7 days after denervation, with significant differences in the Hill coefficients and pCa threshold values in 2- vs. 7-day-denervated fibers. The sarcoplasmic reticulum Ca2+ uptake capacity and rate significantly decreased after 2 days of denervation, whereas both increased at 7 days. Caffeine sensitivity of sarcoplasmic reticulum Ca2+ release was transitory and markedly increased in 2-day-denervated fibers. Our results indicate that type 2B fiber functional properties are highly sensitive to the interruption of nerve supply. Moreover, most of 2-day-denervated changes were reverted at 7 days.

Animals↗

PubMedDate not supplied

Caffeine and length dependence of staircase potentiation in skeletal muscle.

Skeletal muscle sensitivity to Ca2+ is greater at long lengths, and this results in an optimal length for twitch contractions that is longer than optimal length for tetanic contractions. Caffeine abolishes this length dependence of Ca2+ sensitivity. Muscle length (ML) also affects the degree of staircase potentiation. Since staircase potentiation is apparently caused by an increased Ca2+ sensitivity of the myofilaments, we tested the hypothesis that caffeine depresses the length dependence of staircase potentiation. In situ isometric twitch contractions of rat gastrocnemius muscle before and after 10 s of 10-Hz stimulation were analyzed at seven different lengths to evaluate the length dependence of staircase potentiation. In the absence of caffeine, length dependence of Ca2+ sensitivity was observed, and the degree of potentiation after 10-Hz stimulation showed a linear decrease with increased length (DT = 1.47 - 0.05 ML, r2 = 0.95, where DT is developed tension). Length dependence of Ca2+ sensitivity was decreased by caffeine when caffeine was administered in amounts estimated to result in 0.5 and 0.75 mM concentrations. Furthermore, the negative slope of the relationship between staircase potentiation and muscle length was diminished at the lower caffeine dose, and the slope was not different from zero after the higher dose (DT = 1.53 - 0.009 ML, r2 = 0.43). Our study shows that length dependence of Ca2+ sensitivity in intact skeletal muscle is diminished by caffeine. Caffeine also suppressed the length dependence of staircase potentiation, suggesting that the mechanism of this length dependence may be closely related to the mechanism for length dependence of Ca2+ sensitivity.

Animals↗

PubMed2001

A possible solvent effect of adenosine diphosphate influences the binding of 1,N6 ethenoadenosine diphosphate to myosin from skeletal muscle.

Skeletal muscle myosin displays two independent and equivalent binding sites for 1,N6 ethenoadenosine diphosphate, with a dissociation constant of 24.7 microM. MgADP, 10 to 40 microM, behaves as a pure competitive type inhibitor (K(SI)=8-9 microM) for the binding of 1,N6 ethenoadenosine diphosphate to skeletal muscle myosin. On the contrary, the inhibition by MgADP, 0.11-1.54 mM, is neither competitive nor non-competitive nor mixed, as is revealed by the analysis with the general kinetic equation (K.J. Laidler, P.S. Bunting, The Chemical Kinetics of Enzyme Action, 2nd ed., Clarendon, Oxford, 1973, p. 94). To explain our finding we propose that MgADP operates a complex type of inhibition, acting both directly as a competitor for myosin active sites, and indirectly by perturbing the regions of the solvent near to the protein.

Acrylamide↗

PubMed1997

Lactate-proton cotransport in skeletal muscle.

Skeletal muscle and most other tissues possess a membrane transport system mediating a coupled lactate and H+ translocation. Muscle possesses several lactate-proton transporter isoforms of which two have been cloned; however, the main isoform remains to be identified. The isoforms may have different properties and functional roles, but these have not been specifically characterized. The distribution of lactate-proton transport capacity in skeletal muscle is fiber type dependent, with a higher capacity in slow-twitch fibers compared with fast-twitch fibers. During intense muscle activity and in the recovery period, the lactate and H+ effluxes are mainly mediated by the lactate-proton transporter, which reduces the accumulation of lactate in muscle as well as the drop in internal pH suggested to be involved in muscle fatigue. Thus the lactate-proton transporter is of functional importance for pH regulation in association with muscle activity. This carrier is also important for lactate uptake into resting muscle and other tissues; therefore, the carrier distribution is important for the fate of lactate in the body. In addition, the capacity of the lactate-proton transporter can be increased by intense training and is reduced by inactivity; thus the lactate-proton transporter can undergo adaptive changes.

Animals↗