Peripheral Circulation

regulation of vasomotor tone in the microcirculation is essential to ensure adequate tissue oxygenation, particularly when oxygen demand is high, i.e., in skeletal or cardiac muscle during exercise and/or when supply is compromised, i.e., during hypoxia or in the presence of a flow-limiting stenosis

The ability of skeletal muscle to regenerate after injury is well established. In contrast, cardiac muscle is incapable of regeneration and recovery after injury. The aim of the present study was to evaluate and compare the regeneration pattern of cardiac and skeletal muscle after transplantation into a skeletal muscle bed in rats. The following group of transplants were performed at the site prepared by removing the host extensor digitorum longus (EDL) muscle. The first group consisted of cardiac muscle transplanted as one piece or after mincing into 1-mm pieces. The second group included cotransplants of cardiac and skeletal muscle minces that were intermixed. Entire EDL muscle or minced EDL muscle were also transplanted for comparison. Rats were sacrificed 3-30 days after transplantation for morphological analysis. The results demonstrated that skeletal muscle transplants underwent rapid regeneration, and by 30 days the entire muscle was filled with regenerated myofibers. In transplants of cardiac muscle significant inflammation, myocardial degeneration and necrosis were observed. In spite of the necrosis and fibrosis, the presence of a few regenerated myotubes in the outer region was observed. In cardiac and skeletal muscle cotransplants, the inflammation was restricted to cardiac tissue; however, by 30 days the entire cotransplant was filled with regenerated myotubes and myofibers. These results show that skeletal muscle is capable of growth, regeneration, and integration with the cardiac muscle after cotransplantation. Combination of skeletal and cardiac muscle may prove useful in defining the cellular processes necessary for enhancing cardiac repair after injury.

the benefits of exercise and exercise training are numerous, varying from increasing skeletal muscle strength to enhancing cardiovascular and respiratory fitness. These attributes of exercise are key elements to the maintenance of good health and the improvement of athletic performance. But are

Abuse of anabolic androgenic steroids (AASs) by athletes has been increased rapidly in many countries to improve their physical fitness and appearance. The abuses of AASs have been associated with impacts on different systems of the body. The present study was conducted to evaluate the histological changes that occurred in skeletal and cardiac muscles during nandrolone (one of AASs) treatment histologically and immunohistochmically. Forty adult male albino rats were divided into four groups. Group 1; control group, group 2; was treated with nandrolone 5 mg/kg intramuscularly weekly, group 3 was treated with nandrolone10 mg/kg intramuscularly weekly and group 4; was treated with nandrolone 20 mg/kg intramuscularly weekly. All groups were treated for 8 weeks. The specimens from the cardiac and skeletal muscles were processed for histological study using light and electron microscopes and immunohistochemical stain for detection of activated caspase-3 as an indicator for apoptotic changes. The skeletal and cardiac muscles appeared hypertrophied after nandrolone treatment. Lesions ranged from mild to severe muscular changes were also detected depending on the dose. The changes were in the form of variations of fibers size and splitting of some fibers in skeletal muscle as well as myofiber lysis, cellular infiltration, vacuolation, swelling and mitochondrial damage in both skeletal and cardiac muscles. The nuclei appeared hyperchromatic with peripherally clumped chromatin. Expression of caspase-3 was significantly increased in skeletal and cardiac tissues treated with higher doses of nandrolone. It is concluded that nandrolone injection in male albino rats induced hypertrophy and degenerative changes in the skeletal and cardiac muscles which may lead to loss of their functions.

The influence of muscular compression on the blood flow in skeletal muscle has been pondered for many years. Anrep & von Saalfeld (1935) first showed that arterial inflow is reduced during contraction due to compression of the intramuscular vessels, an effect later confirmed by Wesche (1986) in humans. Compression of the veins aids venous return to the heart (Guyton et al. 1962) and has been postulated to increase skeletal muscle perfusion by reducing the downstream venous pressure during relaxation, i.e. the muscle pump effect. Evidence in support of this notion is scanty, but the absence of contraction-induced hyperaemia when vascular smooth muscle relaxation is impaired implies that immediate increases in blood flow are attributable to rapid vasodilatation rather than a muscle pump effect (Hamann et al. 2004). Indeed, there is definitive evidence of rapid vasodilation at the onset of contractions in the rat spinotrapezius muscle (Marshall & Tandon, 1984), hamster cremaster muscle (Mihok & Murrant, 2004), and the hamster retractor muscle (VanTeeffelen & Segal, 2006). An additional way that compression could influence blood flow is through activation of a myogenic-like response. This idea was first put to the test by Mohrman & Sparks (1974) who showed that inflation of a cuff placed around isolated canine gastrocnemius muscle could cause vasodilatation. In addition, they observed that changes in vascular conductance following contraction were related to intramuscular pressure. More recent data demonstrated that brief periods of mechanical compression elicit dilatation in isolated soleus feed arteries (Clifford et al. 2006). The time course of the vasodilatation was remarkably similar to that for the change in blood flow after a brief muscle contraction. In addition, multiple pressure pulses evoked a greater magnitude of dilatation than a singe pressure pulse. On the basis of these results it was suggested that compression of the intramuscular vasculature could provide a mechanism for rapid vasodilatation following contraction. The study by Kirby et al. (2007) in this issue of The Journal of Physiology represents another important landmark in this story. The clever manipulations employed by this group are a superb example of how to study integrative human physiology. Moreover, the results show quite clearly that mechanical compression can elicit hyperaemia in the human forearm. The existence of a dose–response relationship over a range of cuff pressures between 25 and 100 mmHg provides the potential to produce graded vasodilatation in response to graded compression of the vasculature. Importantly, the observation of a temporal dissociation between the peak response to compression and that elicited by contractions argues that mechanical influences do not completely explain contraction-induced vasodilatation. In considering these results, one must keep in mind that it cannot be determined whether the forearm cuff faithfully mimics the compression elicited by forceful muscular contraction. One issue that remains to be resolved is whether this mechanism is operative in all types of muscle under all conditions. Berg et al. (1997) and vanTeeffelen & Segal (2006) maintain that vessel compression is not a factor in thin muscle in situ preparations. However, it must be emphasized that complete collapse of the vessel is not required to evoke this response. In fact, subjects in the study of Kirby et al. with a mean arterial pressure of 89 mmHg exhibited significant dilatation when external pressure was applied at only 50 mmHg. In the in vitro model (Clifford et al. 2006), high extravascular pressures were employed to simulate intramuscular pressures during maximal contraction. More recent experiments (unpublished observations Clifford & Jasperse) reveal that compression-induced dilatation can occur with little discernible reduction in vessel diameter. Substantial dilatation was observed when a brief pressure pulse matching intraluminal pressure was applied to the outside of the vessel. We speculate that contraction of muscle fibres may evoke sufficient vascular compression to elicit dilatation in the in situ muscle preparations. There has been considerable discussion of redundant factors being involved in complex physiological responses such as exercise hyperaemia. The present findings suggest a scenario where there may be temporally distinct phases of vasodilatation. Mechanically induced feed forward vasodilatation could occur with the initial contraction. Vasodilatation could then continue as potassium rapidly accumulates in the interstitium. After sufficient time to allow production and diffusion of metabolites from skeletal muscle, the blood flow could be adjusted by feedback mechanisms to match blood flow with oxygen consumption. A critical challenge for physiologists interested in this topic will be to begin teasing out the time course over which each of these overlapping mechanisms may act. The paper by Kirby et al. (2007) makes a key contribution by demonstrating that mechanically induced vasodilatation is most important in the very initial phase of hyperaemia. Until recently, little consideration has been given to a mechanical mechanism to explain vasodilatation during exercise. Kirby and colleagues have provided the impetus for further study of this mechanism. It seems clear that the influence of mechanical factors must be incorporated into our models for the overall picture of exercise hyperaemia.

Sympathetic nervous system restraint of skeletal muscle blood flow during dynamic exercise has been well documented. However, whether sympathetic restraint of muscle blood flow persists and is constant throughout prolonged exercise has not been established. We hypothesized that both alpha1- and alpha2-adrenergic receptors would restrain skeletal muscle blood flow throughout prolonged constant-load exercise and that the restraint would increase as a function of exercise duration. Mongrel dogs were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. Flow-adjusted doses of selective alpha1- (prazosin) and alpha2-adrenergic receptor (rauwolscine) antagonists were infused after 5, 30, and 50 min of treadmill exercise at 3 and 6 miles/h. During mild-intensity exercise (3 miles/h), prazosin infusion resulted in a greater (P < 0.05) increase in vascular conductance (VC) after 5 [42% (SD 6)], compared with 30 [28% (SD 6)] and 50 [28% (SD 8)] min of running. In contrast, prazosin resulted in a similar increase in VC after 5 [29% (SD 10)], 30 [24% (SD 9)], and 50 [22% (SD 9)] min of moderate-intensity (6 miles/h) exercise. Rauwolscine infusion resulted in a greater (P < 0.05) increase in VC after 5 [39% (SD 14)] compared with 30 [26% (SD 9)] and 50 [22% (SD 4)] min of exercise at 3 miles/h. Rauwolscine infusion produced a similar increase in VC after 5 [19% (SD 3)], 30 [15% (SD 6)], and 50 [16% (SD 2)] min of exercise at 6 miles/h. These results suggest that the ability of alpha1- and alpha2-adrenergic receptors to produce vasoconstriction and restrain blood flow to active muscles may be influenced by both the intensity and duration of exercise.

In this study, the effect of high-calorie feeding and aerobic exercise on skeletal and cardiac muscle citrate synthase (CS), carnitine palmitoyltransferase-I (CPT-I), and -II (CPT-II) mRNA expressions were evaluated. Genetically non-obese rats were grouped as normal-high calorie and sedentary-exercising. Gastrocnemius-soleus and heart muscles' CS, CPT-I, and CPT-II expressions and skeletal muscles' histopathological characteristics were evaluated. High-fat diet had increased body weight by 10% and aerobic exercise did not make any difference. Skeletal muscle CS expression was increased significantly in normal-calorie exercising group. Exercise and high-fat diet did not change CPT-I and CPT-II expressions in both heart and skeletal muscle. Histopathological evaluations demonstrated increased cytoplasmic lipid droplets in high-calorie fed sedentary rats, and exercise had reduced lipid droplets in skeletal muscle. Also, both mitochondria and nuclei distribution were impaired in high-calorie groups. In conclusion, aerobic exercise without food restriction was not enough to make significant changes in fat transportation mechanism into skeletal and heart muscle.

In both cardiac and skeletal muscles, contraction begins when Ca2+ binds to a regulatory site or sites in the N-lobe of troponin (Tn) C. Ca2+ binding to TnC induces sequential protein–protein interactions between TnC and TnI, TnI and TnT, and TnI–TnT and tropomyosin (Tm). As a result, Tm moves along actin (A) molecules exposing the sites for myosin S1 to attach thus leading to contraction. Recent protein biochemical, protein crystal structural, and cell physiology studies have advanced our understanding of the structure and function of myofilament proteins, especially the thin filament proteins (reviewed in Gordon et al. 2000; Kobayashi & Solaro, 2005). It has been demonstrated that for each seven actin monomers, there is one Tm and one Tn (7: 1: 1, A: Tm: Tn), which makes up one regulatory unit (RU). This structural arrangement forms the basis for cooperative interactions not only between Tn–Tm along the thin filament within the unit but also cooperative interactions between near-neighbouring regulatory units when cross-bridges are formed. In fact, it has been hypothesized that 12–14 actin monomers are controlled by one Tn. This hypothesis has recently been supported by Regnier et al. (2002) who have shown that in skeletal muscle, Ca2+-triggered activation of thin filament spread beyond the regulatory unit up to 10–12 actins which compose one functional unit (FU). What about cardiac muscle activation? The sequential events after Ca2+ binding to TnC are very similar in both types of muscles. However, several lines of evidence may indicate that cardiac muscle activates in a unique fashion. (1) The Ca2+ transient during systole may not be long enough to fully activate the thin filament. (2) Cardiac muscle must have a greater sarcomere length dependence of force development due to the narrow range of sarcomere lengths the heart normally works. (3) Cardiac muscle is more responsive to neuro/hormonal stimulation. In this issue of The Journal of Physiology, Gillis et al. (2007) have demonstrated that a cardiac FU in thin filament activation is limited within a RU in that Tn activates ≤ 7 actins upon Ca2+ activation, and that the behaviour of the cardiac FU depends on bound cross-bridges within the RU and is relatively independent of near-neighbour FUs (i.e. greater local control of activation). Although the molecular mechanism for the local control of thin filament activation is not precisely known, these findings indeed highlight the fact that different isoforms of regulatory proteins may be responsible for the differences in thin filament activation between cardiac and fast skeletal muscles. For example, as discussed by Gillis et al. structural and kinetic differences in Ca2+ binding to cTnC, cTnI–cTnC interactions between fast skeletal and cardiac isoforms, as well as more flexible Tm in cardiac muscle could contribute to the differences in RUs between skeletal and cardiac muscle. The findings that cardiac muscle activation is more limited within the RU and has a greater reliance on crossbridge attachment, thus allowing greater and finer local control of activation and force generation, has important implications for pathophysiological states. For example, hypertrophic and dilated cardiomyopathies can be caused by mutations in genes which encode thick or thin filament proteins (Morita et al. 2005). These mutant proteins impact on Ca2+ sensitivity, sarcomere length dependence and also cross-bridge behaviour of the cardiac muscle. Post-translational modifications also impact on thin filament proteins in disease states including degradation and oxidation of myofilament proteins in ischaemia/reperfusion injury which are functionally significant. Finally, cardiac muscle activation is influenced by neuro/hormonal modulation via protein kinase signalling pathways. In heart failure, altered phosphorylation of myofilament proteins may alter cross-bridge dynamics and decrease force production. Precisely how of each of the myofilament proteins contribute to the limited near-neighbour interactions and greater cross-bridge attachment control of activation in cardiac muscle is not known and should be the focus of future investigations. Understanding the molecular properties of these regulatory proteins will no doubt help us to better appreciate the nature of cardiac contraction at both whole organ and cellular level in health and disease.

1. Limited isovolaemic haemodilution was produced in cats by addition of dextran 75-Ringer solution to an extracorporeal blood reservoir connected in series with the cat. Total hepatic venous outflow was neasured using a hepatic venous long-circuit and hepatic arterial flow was measured with an electromagnetic flow probe. Oxygen uptake was monitored in the guts and liver. Na-pentobarbitone anaesthesia was used. 2. Following reduction of the haematocrit (from 31 to 22) the oxygen uptake of the gut segment and liver were maintained. Gut conductance increased to 125% of control while the oxygen extraction ratio increased to only 109%. The hepatic arterial conductance did not change in spite of a greatly reduced (to 68%) oxygen delivery. Hepatic extraction increased to 140% of control. 3. The hepatic artery did not dilate to maintain constant oxygen supply to the liver thus confirming our previous observation that blood flow is not coupled to hepatic metabolism. 4. Oxygen extraction in the gut correlated well with changes in portal blood flow but not with changes in vascular conductance, arterial blood pressure or oxygen delivery. 5. The blood flow of the gut (vascular beds draining into the portal vein in the splenectomized preparation) was controlled in a manner that prevented changes in portal venous PO2 in spite of a reduction in oxygen content. Local PO2 and perhaps pH, are suggested as the factors controlling gut blood flow following haemodilution. 6. Changes in portal blood flow correlated with changes in portal vascular (intrahepatic) conductance such that increased portal flow produced an increased portal conductance thereby maintaining portal venous pressure constant.

Advancing age is associated with changes in fat and carbohydrate (CHO) metabolism, which is considered a risk factor for cardiovascular disease and diabetes. The effects of exercise intensity and duration on fat and CHO metabolism in elderly male subjects were investigated in the present study. Seven trained (63.7+/-4.7 years) and six untrained (63.5+/-4.5 years) healthy males performed three 30 min trials on a cycle ergometer at 50, 60 and 70% VO2max and two other trials at 60 and 70% VO2max in which the total energy expenditure was equal to that for 30 min at 50% VO2max Respiratory measures were undertaken throughout the exercise and blood samples taken before and immediately after each trial. Statistical analyses revealed a significant effect of exercise intensity on fat oxidation when the exercise durations were equated as well as when the energy expenditure was held constant for the three trials, though no training effect was noted. Total carbohydrate oxidation increased significantly with exercise intensity (P<0.05) and with training. Significantly higher levels of non-esterified free fatty acid (NEFA) and glycerol were observed for trained compared with untrained though not for B-hydroxybutyrate (3-OH) or insulin. No differences in NEFA, glycerol, 3-OH were evident for increases in exercise intensity. Carbohydrate and fat oxidation are significantly affected by exercise intensity in elderly males, although only CHO oxidation is influenced by training. Furthermore, training-induced increases in the availability of NEFA and glycerol are not associated with an increase in fat oxidation, rather an increase in CHO oxidation.

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality for patients with diabetes mellitus (DM). Atherosclerosis secondary to DM is a major contributor to DM-related CVD end-points and may predispose to the microvascular (e.g. microangiopathy, peripheral artery disease) and macrovascular (e.g., myocardial infarction, stroke) complications associated with DM. Understanding of the pathogenic mechanisms associated with atherosclerotic DM is important for better management of CVDs. The pathogenesis of atherosclerosis with DM may begin with the vascular endothelium, which is the monolayer of cells lining the inside of blood vessels. Vascular endothelial dysfunction presents early in the atherosclerotic process and is considered to be an early predictor of atherosclerosis. Endothelial dysfunction during the atherosclerotic process may be amplified in patients with DM as a result of chronic hyperglycaemia. Chronic hyperglycaemia is an important pathophysiological stimulant for endothelial dysfunction because it may cause the formation of advanced glycation end-products and increased oxidative stress that can lead to vascular endothelial damage. Acute hyperglycaemia (AH) may provide the initial prompt for endothelial dysfunction, leading to atherogenesis and the micro- and macrovascular injuries associated with DM. AH has been shown to increase oxidative stress in human endothelial cells in vitro and is associated with worsened vascular function in many clinical settings. However, whether it is AH or the underlying conditions associated with AH that are responsible for worsening vascular function is unknown. Previous studies examining the effect of AH on macrovascular endothelial function mostly show a detrimental impact of AH on flow-mediated dilatation (FMD, a measure of endothelial function). However, these findings are complicated by the use of oral glucose and high-carbohydrate meal interventions to induce AH. Autonomic nervous system output, blood pressure changes, gut hormone release and insulin secretion are part of the complex physiological response to glucose ingestion and may be confounding factors in the relationship between AH and macrovascular function. Thus, it is difficult to determine whether changes in endothelial function are a result of AH itself or one of the other complex physiological responses caused by glucose ingestion. Similarly, studies examining the effect of AH on microvascular function have used oral glucose interventions to induce AH, without controlling for other confounding factors that may be influenced by oral glucose ingestion. Although studies are split between improved, unchanged and diminished microvascular functioning in response to AH, the mechanism for these responses is unclear as a result of the potential confounding effects of autonomic output, insulin secretion and incretins. To investigate the effects of AH on micro- and macrovascular function, i.v. glucose-induced AH may be advantageous compared to oral glucose or high-carbohydrate meal interventions because it bypasses the complex physiological responses of oral glucose ingestion to provide a more direct method of determining the effects of AH on the vasculature. In an article recently published in The Journal of Physiology, Horton et al. (2022) utilized a 4 h i.v. glucose infusion (with coadministration of octreotide; OCT) to evaluate the effects of acute hyperglycaemia on arteriolar, microvascular and macrovascular function, with euglycaemic OCT infusion used as a control. Their findings suggest that acute hyperglycaemia may enhance vascular endothelial function, as well as cardiac and skeletal muscle microvascular function, in healthy, young adults. Three measures were utilized to assess macrovascular function during euglycaemia and AH: (i) FMD was used to assess brachial artery endothelial function; (ii) carotid-femoral pulse wave velocity (cfPWV) was used to assess central aortic stiffness; and (iii) post-ischaemic flow velocity (PIFV) of the left forearm was used to assess resistance arteriolar function. FMD did not significantly differ during euglycaemia compared to baseline measures, but was significantly increased during 4 h steady-state AH. Neither cfPWV, nor PIFV significantly changed during euglycaemia or AH compared to baseline. These results suggest that AH does not affect central aortic stiffness or resistance arteriolar function, but may stimulate better endothelial function in healthy, young adults. Cardiac and skeletal muscle microvascular perfusion were assessed during euglycaemia and AH using contrast-enhanced ultrasound at the interventricular septum and left forearm, respectively. Microvascular blood flow (MBF) was quantified using video intensity units, microvascular blood volume (MBV) in 1 s–1, and microvascular flow velocity (MVF) as the product of MBF and MBV, in units of video intensity s–1. In skeletal muscle, there were no significant differences for MBF, MBV or MVF during euglycaemia compared to baseline, although there was a significant increase in MBF, MBV and MVF during AH. In cardiac muscle, MBF, MBV and MVF did not significantly differ between baseline and euglycaemia; however, MBV, but not MBF or MVF, significantly increased during AH compared to baseline. Taken together, these data suggest that OCT infusion during euglycaemia has no effect on cardiac or skeletal microvascular perfusion, and that AH may increase MBV in cardiac and skeletal muscle. Horton et al. (2022) eloquently demonstrated that AH enhances endothelial function, as well as cardiac and skeletal microvascular function, in healthy, young adults. These findings are in contrast to previous studies finding that AH induces vascular dysfunction, although Horton et al. (2022) have noted important differences in their study design that may account for their results. First, Horton et al. (2022) utilized an i.v. method for glucose delivery, thereby bypassing the complex physiological responses associated with oral glucose ingestion. The dysfunctional vascular response to oral glucose ingestion in previous studies may be more reflective of autonomic, insulin and incretin contributions, and utilizing an i.v. glucose delivery method may better isolate the effects of AH and account for the differences in the vascular response. Second, Horton et al. (2022) recruited a population of healthy, young adults, whereas previous studies examined these associations in overweight or older populations. Thus, the enhanced vascular response demonstrated by Horton et al. (2022) may be reflective of their younger and healthier population. Although Horton et al. (2022) propose several notable differences in their study design that may account for their novel findings, another potential characteristic that could have contributed to their results is the exercise status of their participants. Chronic exercise involvement has been shown to lower resting blood viscosity through increases in plasma volume (Connes et al. 2012), and enhance vascular structure and function through long-term increases in blood flow and shear stress (Niebauer & Cooke, 1996). Long-term increases in blood flow and shear stress, resulting from regular physical activity, improve vascular structure through increases in arterial size and distensibility, at the same time as improving vascular reactivity by upregulating nitric oxide (NO) synthase production and increasing NO bioavailability, leading to enhanced vasodilatory pathways. By contrast, long-term sedentary behaviour is associated with higher resting blood viscosity and chronically low mean blood flow and shear stress. The reduced mean blood flow and shear stress causes arterial stiffening, reductions in NO bioavailability and a pro-thrombotic environment, leading to vascular dysfunction and atherosclerosis. Because of differences in resting blood viscosity and vascular structure and function, vascular reactivity to acute changes in blood viscosity may differ between persons with high and low exercise capacity. In persons with high exercise capacity and lower resting blood viscosity, acute increases in blood viscosity may induce laminar shear stress and lead to enhanced vascular function through the upregulation of NO-mediated vasodilatory pathways (Connes et al. 2012). By contrast, persons with lower exercise capacity and high resting blood viscosity may incur endothelial dysfunction in response to acute increases in blood viscosity. Acute increases in blood viscosity may cause increases in blood flow resistance, turbulent blood flow and oscillatory shear stress, promoting endothelial oxidative stress and increasing vasoconstrictive pathways (Niebauer & Cooke, 1996). With that in mind, the enhanced vascular function during AH observed by Horton et al. (2022) may be a result of their participants developing healthy blood and vascular adaptations associated with long-term exercise involvement. AH may induce acute increases in blood viscosity (with increased blood glucose levels being directly related to increased blood viscosity; Irace et al. 2014) to which persons with a higher exercise capacity may be better able to respond to. Indeed, in healthy sportsmen with high exercise capacity, acute increases in blood viscosity were associated with increased NO production and improved vasodilatation, leading to enhanced vascular function (Connes et al. 2012). Horton et al. (2022) note that previous studies observing endothelial dysfunction with AH were condicted in populations that were diseased, obese and ageing. The aforementioned populations have been shown to engage in less exercise training and have increased sedentary behaviour (Zhou et al. 2018), which may further explain the differences in vascular function observed during AH. Future studies should expand on the findings from Horton et al. (2022) by comparing the effects of i.v. induced AH on vascular function in healthy, exercise-trained young adults to healthy, sedentary young adults. In summary, Horton et al (2022) have demonstrated that AH enhances endothelial function, as well as cardiac and skeletal microvascular function, in healthy, young adults. Higher exercise capacity associated with vascular adaptations in healthy, young individuals broadens the basis of knowledge for the relationship between AH intervention and enhanced skeletal muscle microvascular perfusion, cardiac muscle MBV and brachial artery vascular function. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare that they have no competing interests. All authors were responsible for the conception or design of the work; drafting the work or revising it critically for important intellectual content; and approving the final version submitted for publication. All authors agree to be accountable for all aspects of the work. No funding was received.

Purkinje Fibers of the Avian Heart Express a Myogenic Transcription Factor Program Distinct from Cardiac and Skeletal Muscle

Aging is associated with an increase in muscle sympathetic nerve activity. Whether this increased efferent sympathetic nerve activity leads to greater tonic vasoconstriction and reduced blood flow to resting and contracting skeletal muscles in old compared to young has not been clearly established. Therefore, the purpose of the present study was to investigate the effect of aging on α1– and α2–adrenergic receptor mediated restraint of skeletal muscle blood flow. Young (n = 6; 22 ± 3 months) and old (n = 7; 119 ± 22 months) beagles were instrumented chronically with transit‐time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. On separate days, flow‐adjusted doses of selective α1‐ (prazosin; 0.25 ug/ml/min) and α2–adrenergic‐receptor (rauwolscine; 1.25 ug/ml/min) antagonists were infused at rest, and during treadmill running at 2.5 miles/h and 4 miles/h with 2.5% grade. Hindlimb blood flow (HBF) and mean arterial pressure (MAP) were monitored continuously and vascular conductance (VC) was calculated as HBF/MAP. Infusion of prazosin resulted in similar increases in VC (p &gt; 0.05) in young and old beagles at rest (Young 100 ± 43 % ; Old:, 158 ± 84 %) and at 2.5 miles/h (Young 61 ± 28 % ; Old:, 80 ± 25 %) and 4 miles/h with 2.5% grade (Young: 36 ± 28 %; Old: 57 ± 13 %). Rauwolscine infusion also produced similar increases in VC (p &gt; 0.05) in young and old beagles at rest (Young: 64 ± 49 %; Old: 119 ± 60 %) and at 2.5 miles/h (Young: 64 ± 20 %; Old: 86 ± 32 %) and 4 miles/h with 2.5% grade (Young: 49 ± 20 %; Old: 61 ± 11 %). These results demonstrate that α1– and α2‐adrenergic receptor mediated restraint of skeletal of muscle blood flow does not increase in older compared to young beagles at rest or during dynamic exercise.

BackgroundToxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown.MethodsThe effects of DOX treatment with or without pre‐treatment with soluble ACVR2B‐Fc (sACVR2B‐Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)‐treated controls, (2) DOX‐treated mice (DOX), and (3) DOX‐treated mice administered with sACVR2B‐Fc during the experiment (DOX + sACVR2B‐Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome‐wide transcriptomics and mRNA and protein analyses. The combination group was pre‐treated with sACVR2B‐Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B‐Fc.ResultsThe DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53‐p21‐REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3‐fold to 5‐fold increase), transferrin receptor (1.5‐fold increase), and Ccl21 (0.6‐fold to 0.9‐fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18‐fold higher gene expression of myostatin in skeletal muscle compared with the heart.ConclusionsCardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53‐p21‐REDD1 signalling is the main common DOX‐activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles.

Tissue-specific biosynthesis of ϵ- N-monomethyllysine and ϵ- N-trimethyllysine in skeletal and cardiac muscle myosin: A model for the cell-free study of post-translational amino acid modifications in proteins