Phospholamban deficiency does not compromise  exercise capacity

Desai, Kavin; Schauble, Eric; Luo, Wusheng; Kranias, Evangelia G.; Bernstein, Daniel

doi:10.1152/ajpheart.1999.276.4.h1172

Cited by 27 publications

(19 citation statements)

References 15 publications

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“…V O 2 max in untrained mice has been reported to range from ϳ80 to 260 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 , and RER at V O 2 max from 0.91 to 1.28 (13,14,31,32,36,38,40). However, there are differences in these studies regarding test protocols, equipment, body masses, strains, age, sex, and how accustomed the mice were to the methods.…”

Section: Discussionmentioning

confidence: 99%

Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy

Kemi

Loennechen

Wisløff

et al. 2002

Journal of Applied Physiology

237

265

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. Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy. J Appl Physiol 93: 1301-1309. First published May 24, 2002 10.1152/japplphysiol.00231.2002-Whereas novel pathways of pathological heart enlargement have been unveiled by thoracic aorta constriction in genetically modified mice, the molecular mechanisms of adaptive cardiac hypertrophy remain virtually unexplored and call for an effective and wellcharacterized model of physiological mechanical loading. Experimental procedures of maximal oxygen consumption (V O2 max) and intensity-controlled treadmill running were established in 40 female and 36 male C57BL/6J mice. An inclination-dependent V O2 max with 0.98 test-retest correlation was found at 25°treadmill grade. Running for 2 h/day, 5 days/wk, in intervals of 8 min at 85-90% of V O2 max and 2 min at 50% (adjusted to weekly V O2 max testing) increased V O2 max to a plateau 49% above sedentary females and 29% in males. Running economy improved in both sexes, and echocardiography indicated significantly increased left ventricle posterior wall thickness. Ventricular weights increased by 19-29 and 12-17% in females and males, respectively, whereas cardiomyocyte dimensions increased by 20-32, and 17-23% in females and males, respectively; skeletal muscle mass increased by 12-18%. Thus the model mimics human responses to exercise and can be used in future studies of molecular mechanisms underlying these adaptations. maximal oxygen uptake; work economy; respiratory exchange ratio; cardiomyocyte; allometric scaling SEVERAL NOVEL SIGNALING PATHWAYS of pathological cardiac hypertrophy have been unveiled in the powerful model of mechanical overloading by thoracic aorta constriction in genetically modified mice (8,22). Thus far, the molecular mechanisms of adaptive cardiac hypertrophy in response to physiological stimuli remain virtually unexplored because of a paucity of effective and well-controlled experimental models in this species. Ideally, the outcome should mimic typical results of exercise training in humans, e.g., increased maximal oxygen uptake (V O 2 max ) and work economy (21). In healthy individuals, increased exercise capacity is dependent on functional and structural adaptations in skeletal muscle, blood vessels, and heart. Cardiac adaptation includes increased ventricular chamber volumes and weights, cardiomyocyte hypertrophy, increased cardiac output, and improved contractile function measured in isolated cardiomyocytes and in the intact heart (2, 3).At present, there are few well-controlled endurance training studies in mice. Training is usually carried out as voluntary exercise regimens, with little control of exercise intensity and the individual's fitness level. Voluntary wheel running is most frequently used. V O 2 max has been shown to increase by 12-30% after a 7-to 12-wk period of free wheel running (11,40). The latter study also demonstrated a 6% decreased respiratory exchange ratio (RER) at V O 2 max in trained mice. Exercise capacity and adaptations have al...

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Section: Discussionmentioning

confidence: 99%

Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy

Kemi

Loennechen

Wisløff

et al. 2002

Journal of Applied Physiology

237

265

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“…Consistent with this notion, reversal of PLN inhibitory activity by in vivo cardiac adenoviral gene delivery improves cardiac function in the cardiomyopathic hamster (10), and mice deficient in PLN demonstrate enhanced Ca 2+ reuptake, increased Ca 2+ -transient amplitude, and improved contractility (11)(12)(13). In the PLN-null mouse, supernormal cardiac function is a permanent feature that does not, over time, compromise exercise endurance or abbreviate life span (13,14). In human hearts, however, chronic cardiac hypercontractily has been implicated as a cause of dilated cardiomyopathy (15,16).…”

mentioning

confidence: 82%

Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human

Haghighi¹,

Kolokathis²,

Pater³

et al. 2003

J. Clin. Invest.

159

172

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In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca2+-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy

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“…Mice were subjected to supervised, graded treadmill exercise by staged, 3-min increases in belt speed (2.5 m/min) until exhaustion. Exhaustion was defined as the mouse spending >50% of the time or >10 consecutive seconds on the shock grid (Desai et al 1999). Up to six animals were exercised simultaneously.…”

Section: Exercisementioning

confidence: 99%

Pleiotropy, Homeostasis, and Functional Networks Based on Assays of Cardiovascular Traits in Genetically Randomized Populations

Nadeau¹,

Burrage²,

Restivo³

et al. 2003

Genome Res.

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A major problem in studying biological traits is understanding how genes work together to provide organismal structures and functions. Conventional reductionist paradigms attribute functions to particular proteins, motifs, and amino acids. An equally important but harder problem involves the synthesis of data at fundamental levels of biological systems to understand functionality at higher levels. We used subtle, naturally occurring, multigenic variation of cardiovascular (CV) properties in a panel of genetically randomized strains that are derived from the A/J and C57BL/6J strains of mice to perturb CV functions in nonpathologic ways. In this proof-of-concept study, computational analysis correctly identified the known relations among CV properties and revealed functionality at higher levels of the CV system. The network was then used to account for pleiotropies and homeostatic responses in single gene mutant mice and in mice treated with a pharmacologic agent (anesthesia). The CV network accounted for functional dependencies in complementary ways to the insights obtained from genetic networks and biochemical pathways. These networks are therefore an important approach for defining and characterizing functional relations in complex biological systems in health and disease.

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Phospholamban deficiency does not compromise exercise capacity

Cited by 27 publications

References 15 publications

Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy

Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy

Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human

Pleiotropy, Homeostasis, and Functional Networks Based on Assays of Cardiovascular Traits in Genetically Randomized Populations

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