Search

Cardiovascular disease is a leading cause of morbidity and mortality, and exercise-training (TRN) is known to reduce risk factors and protect the heart from ischemia and reperfusion injury. Though the cardioprotective effects of exercise are well-documented, underlying mechanisms are not well understood. This review highlights recent findings and focuses on cardiac factors with emphasis on K+ channel control of the action potential duration (APD), β-adrenergic and adenosine regulation of cardiomyocyte function, and mitochondrial Ca2+ regulation. TRN-induced prolongation and shortening of the APD at low and high activation rates, respectively, is discussed in the context of a reduced response of the sarcolemma delayed rectifier potassium channel (IK) and increased content and activation of the sarcolemma KATP channel. A proposed mechanism underlying the latter is presented, including the phosphatidylinositol-3kinase/protein kinase B pathway. TRN induced increases in cardiomyocyte contractility and the response to adrenergic agonists are discussed. The TRN-induced protection from reperfusion injury is highlighted by the increased content and activation of the sarcolemma KATP channel and the increased phosphorylated glycogen synthase kinase-3β, which aid in preventing mitochondrial Ca2+ overload and mitochondria-triggered apoptosis. Finally, a brief section is presented on the increased incidences of atrial fibrillation associated with age and in life-long exercisers. [ABSTRACT FROM AUTHOR]

Patients with two congenital heart diseases (CHDs), Ebstein’s anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the “structural constituent of muscle” pathway was suppressed, whereas the “ER lumen” pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation. NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein’s anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling. [ABSTRACT FROM AUTHOR]

The single chemically skinned type I muscle fibers isolated from rat, rhesus monkey and human soleus and gastrocnemius muscles were analyzed to determine their contractile properties under similar experimental conditions. Analysis of the type I myosin heavy chain-expressing muscle fibers under sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated the presence of minute differences in peak tension. Furthermore, the unloaded shortening velocity of the soleus muscles were similar in all species.

Single gastrocnemius muscle fibres from master runners (RUN) and sedentary (SED) males show different force-power and force-velocity properties due to difference in the expression of myosin heavy chain (MHC) isoforms. MHC type I and type IIa fibres of the RUN group are smaller in diameter and have 13% and 27% lower peak isometric power output respectively than those of the SED males. The fibres from both SED and RUN groups have similar type I and IIa V(sub max); and a/P(sub o), where a is a constant with dimensions of force and P(sub o) is peak isometric force.

The maximal shortening velocity (V(sub o)) and isometric tension (P(sub o)) of single gastrocnemius fibres from endurance-trained master runners (RUN) reveal that the muscles have contractile and morphological properties that enhance prolonged performance. Maximal Ca2+ activation causes a 15% decline in the peak absolute force of the slow type I and the fast type IIa fibres, and a 19% increase in type I fibre V(sub o). P(sub o) and elastic modulus is similar in RUN and sedentary-life style individuals. The RUN individuals have a higher expression of myosin light chain isoforms in their fibres.

Age-induced declines in skeletal muscle contractile function have been attributed to multiple cellular factors, including lower peak force (Po), decreased Ca2+ sensitivity, and reduced shortening velocity (Vo). However, changes in these cellular properties with aging remain unresolved, especially in older women, and the effect of submaximal Ca2+ on contractile function is unknown. Thus, we compared contractile properties of muscle fibers from 19 young (24 ± 3 yr; 8 women) and 21 older adults (77 ± 7 yr; 7 women) under maximal and submaximal Ca2+ and assessed the abundance of three proteins thought to influence Ca2+ sensitivity. Fast fiber cross-sectional area was ~44% larger in young (6,479 ± 2,487 μm2 ) compared with older adults (4,503 ± 2,071 μm2 , P < 0.001), which corresponded with a greater absolute Po (young = 1.12 ± 0.43 mN; old = 0.79 ± 0.33 mN, P < 0.001). There were no differences in fast fiber size-specific Po, indicating the age-related decline in force was explained by differences in fiber size. Except for fast fiber size and absolute Po, no age or sex differences were observed in Ca2+ sensitivity, rate of force development (ktr), or Vo in either slow or fast fibers. Submaximal Ca2+ depressed ktr and Vo, but the effects were not altered by age in either sex. Contrary to rodent studies, regulatory light chain (RLC) and myosin binding protein-C abundance and RLC phosphorylation were unaltered by age or sex. These data suggest the age-associated reductions in contractile function are primarily due to the atrophy of fast fibers and that caution is warranted when extending results from rodent studies to humans. [ABSTRACT FROM AUTHOR]

Exercise training is known to prolong the ventricular cardiomyocyte action potential duration (APD), increasing Ca2+ influx and contractility. The prolonged APD is caused, in part, by a decreased responsiveness to β-adrenergic agonists. The study’s aims were to elucidate the mechanisms by which exercise training alters -adrenergic regulation and to determine the involvement of delayed rectifier potassium channels (lKr and lKs) in the response. Rats were randomly assigned to wheel running-trained (TRN) or sedentary (SED) groups. After 6 – 8 wk of training, myocytes were isolated from the apex and base regions of the left ventricle, and current–voltage relationships of lKr and lKs were measured. Myocytes from SED and TRN rats exhibit lower lKr current compared with lKs, and a regional difference in lKs was observed, with higher current in apex compared with base myocytes. Wheel running decreased lKs at positive voltages and reduced lKs responsiveness to β-agonist. lKs channel subunit KCNQ1 content was higher in apex compared with base, and exercise training decreased KCNQ1 and KCNE1 subunit content in both regions. Exercise training had no effect on β1-adrenergic receptor content but reduced the kinase anchoring protein yotiao and β-adrenergic receptor kinase GRK2 compared with SED rats. The reduced KCNQ1, KCNE1, and yotiao provide a mechanism underlying the training-induced decrease in lKs current, while downregulation of GRK2 would reduce inactivation of the β1-AR, maintaining adrenergic stimulation of contractility. Collectively, these membrane protein changes in response to TRN provide a mechanism for prolonging the APD, increasing myocyte efficiency in low stress conditions, while increasing contractility. NEW & NOTEWORTHY Results demonstrate that exercise training (TRN) downregulates ventricular lKs channel current and the channel’s responsiveness to -agonist factors mediated by TRN-induced decline in channel subunits KCNQ1 and KCNE1 and the A-kinase anchoring protein yotiao. The reduced lKs current helps explain the TRN-induced prolongation of the action potential in basal conditions and, coupled with previously reported upregulation of the KATP channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism. [ABSTRACT FROM AUTHOR]

Fitts, Robert H., Dominique Desplanches, Janell G. Romatowski, and Jeffrey J. Widrick. Spaceflight effects on single skeletal muscle fiber function in the rhesus monkey. Am J Physiol Regulatory Integrative Comp Physiol 279: R1546-R1557, 2000.-- The purpose of this investigation was to understand how 14 days of weightlessness alters the cellular properties of individual slow- and fast-twitch muscle fibers in the rhesus monkey. The diameter of the soleus (Sol) type I, medial gastrocnemius (MG) type I, and MG type II fibers from the vivarium controls averaged 60 [+ or -]1, 46 [+ or -] 2, and 59 [+ or -] 2 [Mu]m, respectively. Both a control 1-G capsule sit (CS) and spaceflight (SF) significantly reduced the Sol type I fiber diameter (20 and 13%, respectively) and peak force, with the latter declining from 0.48 [+ or -] 0.01 to 0.31 [+ or -] 0.02 (CS group) and 0.32 [+ or -] 0.01 mN (SF group). When the peak force was expressed as kiloNewtons per square meter (kN/[m.sup.2]), only the SF group showed a significant decline. This group also showed a significant 15% drop in peak fiber stiffness that suggests that fewer cross bridges were contracting in parallel. In the MG, SF but not CS depressed the type I fiber diameter and force. Additionally, SF significantly depressed absolute (mN) and relative (kN/[m.sup.2]) force in the fast-twitch MG fibers by 30% and 28%, respectively. The [Ca.sup.2+] sensitivity of the type I fiber (Sol and MG) was significantly reduced by growth but unaltered by SF. Flight had no significant effect on the mean maximal fiber shortening velocity in any fiber type or muscle. The post-SF Sol type I fibers showed a reduced peak power and, at peak power, an elevated velocity and decreased force. In conclusion, CS and SF caused atrophy and a reduced force and power in the Sol type I fiber. However, only SF elicited atrophy and reduced force (mN) in the MG type I fiber and a decline in relative force (kN/[m.sup.2]) in the Sol type I and MG type II fibers. contractile properties; morphology; slow twitch; fast twitch

Exercise training is known to protect the heart from ischemia and improve function during exercise by reducing cardiomyocyte action potential duration (APD) and increasing contractility. The cellular mechanisms involve β-adrenergic regulation and the ATP-sensitive K+ (KATP) channel, but how each alters function of the left ventricle and sex specificity is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to wheel-running (TRN) or sedentary (SED) groups. After 6-8 wk of training, myocytes were isolated from the left ventricle and field stimulated at 1, 2, and 5 Hz. TRN significantly increased cardiomyocyte contractility, the kinetics of the Ca2+ transient, and responsiveness to the adrenergic receptor agonist isoproterenol (ISO), as reflected by an increased sarcomere shortening. Importantly, we demonstrated a TRN-induced upregulation of KATP channels, which was reflected by elevated content, current density, and the channel's contribution to APD shortening at high activation rates and in the presence of the activator pinacidil. TRN induced increase in KATP current occurred throughout the left ventricle, but channel subunit content showed regional specificity with increases in Kir6.2 in the apex and SUR2A in base regions. In summary, TRN elevated cardiomyocyte cross-bridge kinetics, Ca2+ sensitivity, and the responsiveness of contractile function to β-adrenergic receptor stimulation in both sexes. Importantly, upregulation of the KATP channel accelerates repolarization and shortens APD during stress and exercise. These adaptations have clinical importance, as increased contractility and reduced APD would help protect cardiac output and reduce intracellular Ca2+ overload during stresses such as regional ischemia. [ABSTRACT FROM AUTHOR]

Key points: The mechanisms responsible for the loss in muscle power and increased fatigability with ageing are unresolved. We show that the contractile mechanics of fibres from the vastus lateralis of old men were well‐preserved compared to those of young men, but the selective loss of fast myosin heavy chain II muscle was strongly associated with age‐related decrements in whole‐muscle strength and power. We reveal that the combination of acidosis (H+) and inorganic phosphate (Pi) is an important mediator of muscle fatigue in humans by inhibiting the low‐ to high‐force state of the cross‐bridge cycle and peak power, but the depressive effects of these ions on cross‐bridge function were similar in fibres from young and old men. These findings suggest that the age‐related loss in muscle power is primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. Abstract: The present study aimed to identify the mechanisms responsible for the loss in muscle power and increased fatigability with ageing by integrating measures of whole‐muscle function with single fibre contractile mechanics. After adjusting for the 22% smaller muscle mass in old (73–89 years, n = 6) compared to young men (20–29 years, n = 6), isometric torque and power output of the knee extensors were, respectively, 38% and 53% lower with age. Fatigability was ∼2.7‐fold greater with age and strongly associated with reductions in the electrically‐evoked contractile properties. To test whether cross‐bridge mechanisms could explain age‐related decrements in knee extensor function, we exposed myofibres (n = 254) from the vastus lateralis to conditions mimicking quiescent muscle and fatiguing levels of acidosis (H+) (pH 6.2) and inorganic phosphate (Pi) (30 m m). The fatigue‐mimicking condition caused marked reductions in force, shortening velocity and power and inhibited the low‐ to high‐force state of the cross‐bridge cycle, confirming findings from non‐human studies that these ions act synergistically to impair cross‐bridge function. Other than severe age‐related atrophy of fast fibres (−55%), contractile function and the depressive effects of the fatigue‐mimicking condition did not differ in fibres from young and old men. The selective loss of fast myosin heavy chain II muscle was strongly associated with the age‐related decrease in isometric torque (r = 0.785) and power (r = 0.861). These data suggest that the age‐related loss in muscle strength and power are primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. [ABSTRACT FROM AUTHOR]

Regular exercise-training is known to affect the action potential duration (APD) and improve heart function, but the involvement by β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K+ (KATP) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel running or control groups and after 6-8 weeks training anesthetized and myocytes isolated. Exercise-training significantly increased APD of apex and base myocytes at 1Hz, while decreasing the APD at 10Hz. Ca2+ transient durations reflected the changes observed in APD, while Ca2+ transient amplitudes were unaffected by wheel running. The non-selective β agonist Isoproterenol (ISO) shortened the myocyte APD an effect reduced by wheel running. The ISO-induced shortening of the APD was largely reversed by selective β1-AR blocker Atenolol, but not the β2-AR blocker ICI 118,551 providing evidence that wheel running reduced the sensitivity of the β1-AR. At 10Hz, the KATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained compared to controls implicating a role for this channel in the exercise-induced APD shortening at 10Hz. A novelty of this work is the demonstration of the duel importance of altered β1-AR responsiveness and KATP channel function in the training-induced regulation of the APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates where sympathetic drive is low by prolonging the APD and Ca2+ influx, while during exercise an increased KATP channel activity would shorten APD thus protecting the heart against Ca2+ overload or inadequate filling. [ABSTRACT FROM AUTHOR]