Cardiovascular, energetics and disease

[Guest guest]

Hi All,

We as CRers are aware that our capacity for

exercise decreases with CR, but our disease

risk factors are reduced.

Now, the pdf available review and paper

below appears to indicate that, for those who

peter out before others during exercise, they are

more disposed to diseases and have the poor

cardiovascular risk markers and proteins important

for mitochondrial functions.

We do know that there are those among us who

have superior athletic performance and appear to

have improved health risk indicators.

Does CR impact on the results of the findings?

The study was in rats. It certainly was a

" prospective " study, in that there was 347% greater

distance to exhaustion of the strain of rats

selected for emergence after artificial selection

for high versus low aerobic capacity. After the

selection, the health risk indicators were examined.

First, here is the review.

Marx J.

Medicine. Low-power mitochondria may raise risk of cardiovascular

problems.

Science. 2005 Jan 21;307(5708):334-5. No abstract available.

PMID: 15661980 [PubMed - in process]

Try as we might, only an elite few will ever win the Tour de

France or even the local 10-K foot race. People simply vary widely in

their ability to perform aerobic exercise. New work with rats now

suggests that individuals with a low tolerance for aerobic exercise

may have a lot more to worry about than just their inability to run

fast and long. The same underlying defect that reduces aerobic

capacity may also predispose a person to a witch's brew of medical

problems that could increase the possibility of heart attacks and

strokes.

On page 418, a research team including Ulrik Wisløff of the

Norwegian University of Science and Technology in Trondheim,

Najjar of the Medical College of Ohio in Toledo, and Britton

of the University of Michigan, Ann Arbor, reports that rats that have

been selectively bred to have reduced capacity for aerobic exercise

show obesity, resistance to the hormone insulin (a sign of type II

diabetes), and high blood pressure, all symptoms of the so-called

metabolic syndrome that raises the risk of cardiovascular disease.

The researchers also provide evidence that impaired function of the

mitochondria, small structures that produce most of a cell's energy,

underlies the metabolic problems of the rats with low aerobic

capacity.

Previous work had implicated poor mitochondrial function with

individual components of metabolic syndrome, but this is the first

time researchers have linked it to all of them at once. " This is an

incredibly provocative study, " says Vamsi Mootha of Massachusetts

General Hospital in Boston, whose own work has linked mitochondrial

malfunction to type II diabetes. " They linked metabolic syndrome to

mitochondria in a way that hasn't been done before. "

Running for their lives. These rats, bred to have high aerobic

capacity, appear to have fewer cardiovascular risk factors than their

couch-potato cousins. CREDIT: MARTIN VLOET/UNIVERSITY OF MICHIGAN

PHOTO SERVICES

The rat-breeding experiments began in 1996, motivated mainly,

Britton recalls, by dissatisfaction with existing animal models for

diabetes and cardiovascular disease. Most of those models were

created by very nonphysiological means, such as tying off the

arteries of the heart or administering a drug that destroys the

insulin-producing cells of the pancreas, far removed from the way the

conditions develop naturally.

To produce animals whose diseases more closely mimic those in

humans, the researchers selectively bred rats to have either high or

low capacity for aerobic exercise. They identified rats with a high

capacity to run on a treadmill and mated them with one another, and

they did the same for animals with a low running capacity. " Since

oxygen metabolism is such a large part of biology, defects in it

should underlie our pathology, " explains Britton.

The animals described in the current report, the products of 11

generations of selective breeding, have a 350% difference in their

running abilities. And by every measure tested, the couch-potato rats

rank high on the cardiovascular risk factor scale: Compared to high-

capacity runners, they are more obese, have higher blood pressures

and higher levels of blood fats, and have increased insulin

resistance.

Although obesity itself can decrease aerobic running capacity, a

statistical analysis showed that it accounts for no more than 20% of

the decreased aerobic capacity. Indeed, studies of very young rats

who were poor exercisers showed that metabolic changes, such as

increased blood concentrations of fat and the sugar glucose, occurred

before any weight differences became apparent.

Because mitochondria provide the energy for exercise, Britton and

his colleagues examined whether these organelles exhibited signs of

reduced function in the low-aerobic-capacity rats. The researchers

found that muscle from those rats had much lower concentrations of a

number of key mitochondrial proteins than did muscle from the high-

capacity animals. This indicates that they had either fewer

mitochondria or less effective ones.

The work provides " a strong link between aerobic capacity,

mitochondrial function, and the full range of cardiovascular

symptoms, " says Flier, an obesity and metabolism expert at

Beth Israel Deaconess Medical Center in Boston. " If you happen to

have drawn the wrong genes, you may be subject to not only not being

a long-distance runner but also to diabetes and cardiovascular

disease. "

All the researchers stress that the results should not be cause

for despair among people who suspect that their own aerobic capacity

may be on the low side. Wisløff's team is testing whether regular

exercise can reduce the various risk factors in the low-aerobic-

capacity rats, and early results look promising, Britton says. So

rather than providing an excuse for sticking to the couch, the new

data could well be yet another reason to hit the bike trail or

aerobic floor.

Now, here are the article excerpts.

Wisloff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share

Q, Fernstrom

M, Rezaei K, Lee SJ, Koch LG, Britton SL.

Cardiovascular risk factors emerge after artificial selection for

low aerobic

capacity.

Science. 2005 Jan 21;307(5708):418-20.

PMID: 15662013 [PubMed - in process]

In humans, the strong statistical association between fitness and

survival suggests a link between impaired oxygen metabolism and

disease. We hypothesized that artificial selection of rats based on

low and high intrinsic exercise capacity would yield models that also

contrast for disease risk. After 11 generations, rats with low

aerobic capacity scored high on cardiovascular risk factors that

constitute the metabolic syndrome. The decrease in aerobic capacity

was associated with decreases in the amounts of transcription factors

required for mitochondrial biogenesis and in the amounts of oxidative

enzymes in skeletal muscle. Impairment of mitochondrial function may

link reduced fitness to cardiovascular and metabolic disease.

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Several investigations link aerobic metabolism to the pathogenesis of

cardiovascular disease. Large-scale epidemiological studies of

subjects with and without cardiovascular disease demonstrate that low

aerobic exercise capacity is a stronger predictor of mortality than

other established risk factors (1–4). In patients with type 2

diabetes, low aerobic capacity is associated with reduced expression

of genes involved in oxidative phosphorylation (5). In insulin-

resistant elders, there is a 40% reduction in mitochondrial oxidative

and phosphorylation activity, largely attributable to impaired

skeletal muscle glucose metabolism (6). These observations are

consistent with impaired regulation of mitochondrial function as an

important mechanism for low aerobic capacity and cardiovascular risk

factors linked to the metabolic syndrome. These risk factors include

weight gain, high blood pressure, reduced endothelial function,

hyperinsulinemia, and increased triglyceride concentration in blood.

The working hypothesis of the present study was that rats selected on

the basis of low versus high intrinsic exercise performance would

also differ in maximal oxygen uptake, mitochondrial oxidative

pathways, and cardiovascular risk factors linked to the metabolic

syndrome.

In previous work, we began large-scale artificial selection for low

and high aerobic treadmill-running capacity with the genetically

heterogeneous N:NIH stock of rats as the founder population (7).

Eleven generations of selection produced low-capacity runners (LCRs)

and high-capacity runners (HCRs) that differed in running capacity by

347% (Fig. 1A). The founder population had a capacity to run for

355±144 m (23.1 min) until exhausted. On average, the treadmill-

running capacity decreased 16 m per generation in LCRs and increased

41 m per generation in HCRs in response to selection. At generation

11, the LCRs averaged 191±70 m (14.3 min), and the HCRs ran for

853±315 m (41.6 min). For this study, we used young adult rats (ages

16 to 24 weeks) derived from generations 10 and 11 to test our

hypothesis that risk factors for common diseases segregate with

variation in intrinsic aerobic capacity (8).

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High blood pressure is associated with increased risk for stroke

and ischemic heart disease (9). We found that, relative to the HCRs,

the LCR rats had higher mean blood pressures during the day (105±13

mm Hg compared with 89±8 mm Hg), at night (98±3 mm Hg compared with

91±7 mm Hg), and for the combined 24-hour period (102±6 mm Hg

compared with 90±7 mm Hg) (Fig. 1B). Extrapolating from human data

(9), this 13% higher 24-hour blood pressure suggests that the LCRs

are twice as likely to develop cardiovascular disease as the HCRs.

Endothelial dysfunction is an independent predictor of long-term

cardiovascular disease progression and cardiovascular event rates

(10). To assess endothelial function in the two strains of rats, we

assayed nitric oxide–mediated (acetylcholine) vascular relaxation in

isolated ring segments of carotid arteries. In this assay, higher

vessel relaxation is interpreted as better endothelial function. For

maximal absolute relaxation, the HCR rats demonstrated a 48% increase

compared with the LCR rats. Furthermore, the concentration of

acetylcholine that provoked a half-maximal response [median effective

concentration (EC50)] was 7.8-fold greater in LCR than HCR rats (Fig.

1C and fig. S1).

LCR rats were insulin-resistant compared with the HCR rats, as

demonstrated by higher fasting insulin levels and impaired glucose

tolerance (Table 1 and fig. S2). Insulin C-peptide levels were normal

in LCR rats, indicating that insulin secretion was preserved.

However, insulin clearance was reduced in the LCR rats, as indicated

by lower steady-state C-peptide/insulin molar ratios. These data

indicate that hyperinsulinemia results mainly from reduced insulin

clearance. Consistent with the clinical scenario of the metabolic

syndrome, the LCR rats also had more visceral adiposity, higher

plasma triglycerides, and elevated plasma free fatty acids compared

with the HCR rats (Table 1).

Table 1. LCR and HCR rats differed significantly for carbohydrate

and lipid metabolic measures. Measurements were taken from male LCR

(n = 8) and HCR (n = 8) rats. Blood was drawn at 0900 hours with food

and water ad libitum to measure random blood sugar. Other metabolic

measures were made on blood drawn after 12 hours of food and water

deprivation.

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LCR HCR % Difference LCR vs. HCR P value

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Random glucose (mg/dl) 86±6 75±12 15% 0.036

Fasting glucose (mg/dl) 110±9 92±5 20% 0.0007

Insulin (pM) 684±195 296±172 131% 0.002

C-peptide (pM) 1590±338 1077±565 48% 0.061

C-peptide/insulin 2.4±0.4 3.8±1.2 -58% 0.013

Visceral adiposity/body weight (%) 1.55±0.39 0.95±0.32 63%

0.005

Triglycerides (mg/dl) 67±24 25±4 168% 0.013

Free fatty acids (meq/l) 0.64±0.22 0.33±0.04 94% 0.031

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Because individuals with cardiovascular disease often show

diminished capacity for adaptation to exercise training (11), we

measured 12 variables to assess the general exercise capacity and

left ventricular function both in sedentary control © and in

exercise-trained (T) LCR and HCR rats (Table 2). Each rat was trained

for 6 weeks on a treadmill at an intensity relative to its own

individual maximal oxygen consumption (VO2max) (12). Consistent with

a low tolerance for exercise, the C-LCR rats had a 58% lower VO2max,

a 17% lower economy of running (i.e., higher oxygen cost of running),

23% less left ventricular weight, and a trend (P = 0.07) toward

shorter left ventricular cell length compared with the C-HCR rats.

Isolated left ventricular cells from C-HCR rats had better systolic

and diastolic function relative to the C-LCR rats (Table 2). In

response to training, both T-LCR and T-HCR rats showed significant

improvement in all 12 of the measures of capacity (Table 2), with a

uniformly greater training response in the T-HCR relative to the T-

LCR rats for each measure except cell width.

Table 2. Exercise capacity and isolated left ventricular cell

variables for LCR and HCR rats separated in groups of sedentary

control © and exercise-trained (T). Before exercise, the C-LCR and

C-HCR rats differed significantly (indicated by asterisks for P <

0.01) for all variables except left ventricular cell length and

width. Six weeks of exercise training significantly improved each of

these 11 variables in both T-LCR and T-HCR rats (indicated by for P

< 0.01). In each case except cell width, T-HCR rats improved more

than T-LCR rats with training ( for P < 0.05). PS, percentage cell

shortening. Values are means±1 SD from six LCR and six HCR female

rats.

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C-LCR C-HCR % Difference % Change with training

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C-LCR vs. C-HCR C-LCR vs. T-LCR C-HCR vs. T-HCR

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Whole animal variables

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VO2max (ml kg-0.75 min-1) 43±2 68±3 -58%* 38% 44%

Economy of running (ml O2 kg-0.75 m-1) 4.9±0.1 4.2±0.2 17%* -

7% -17%

Left ventricular weight (mg kg-0.75) 1561±176 1917±88 -23%*

22% 27%

Left ventricular cell variables

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Cell length (µm) 118±2 124±2 -5% 6% 14%

Cell width (µm) 23±3 19±3 20% 2% 2%

Systolic cell function

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Cell shortening (%) 14.0±1.2 17.1±1.1 -22%* 30% 39%

Relative time to peak shortening (ms PS-1) 2.7±0.2 2.3±0.2 17%

* -24% -32%

Systolic [Ca2+] (µM) 1.61±0.03 1.73±0.04 -7%* -16% -23%

Amplitude of [Ca2+] transient (µM) 1.20±0.03 1.38±0.05 -15%* -

19% -24%

Diastolic cell function

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Time to 50% relengthening (ms) 39.9±1.2 35.2±1.3 13%* -14% -

16%

Diastolic [Ca2+] (µM) 0.41±0.02 0.35±0.02 17%* -7% -20%

Time to 50% decay of [Ca2+] transient (ms) 55.3±1.4 45.9±1.3 20%

* -11% -13%

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Mitochondrial dysfunction is associated with a wide range of human

diseases (5). In view of the lower aerobic capacity and reduced

cardiovascular function of LCR rats, we hypothesized that they have

compromised mitochondrial oxidative function relative to the HCR

rats. To test this hypothesis, we measured the cellular content of

proteins required for mitochondrial biogenesis and function (5, 13)

in soleus muscle, which is composed largely of highly oxidative

fibers. The amounts of peroxisome proliferative activated receptor

(PPAR-), PPAR- coactivator 1 (PGC-1), ubiquinol-cytochrome c

oxidoreductase core 2 subunit (UQCRC2), cytochrome c oxidase subunit

I (COXI), uncoupling protein 2 (UCP2), and ATP synthase H+-

transporting mitochondrial F1 complex (F1-ATP synthase) were markedly

reduced in the LCR rats in comparison with the HCRs. The uniform

decline in these proteins is consistent with the hypothesis that

reduced aerobic metabolism plays a causal role in the development of

the differences between the LCR and HCR rats (Fig. 2). PGC-1,

particularly because it interacts with PPAR-, seems to be centrally

positioned for influencing both energy metabolism and the progression

of complex diseases. PGC-1 is a transcriptional coactivator involved

in energy transfer pathways and mitochondrial biogenesis and permits

PPAR- to interact with many transcription factors (14). PPAR-, a

regulator of adipocyte differentiation, has been implicated in the

pathology of numerous diseases including obesity and diabetes.

Thiazolidinediones are selective ligands of PPAR- and effective for

the treatment of type 2 diabetes, suggesting a pivotal role for PPAR-

in complex diseases (15).

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Body weight can have a substantial influence on both aerobic

running capacity and the emergence of disease (16). Eleven

generations of selective breeding for running capacity produced a

correlated change in body weight. By generation 11, male LCR rats

weighed 92 g more (39%) than HCR males, and similarly the LCR female

rats weighed 44 g more (24%) than HCR females (fig. S3). Multiple

regression analysis using weight and generation as predictors of

running capacity revealed that changes in body weight explained 7% of

the variation in distance run in HCR females, 7% in LCR females, 20%

in HCR males, and 14% in LCR males. Thus, factors other than body

weight account for the majority of the variation in distance run

across the 11 generations of selection in both strains.

Because risk factors for complex diseases often emerge with aging

(17), we measured indices of metabolic risk in 5-week-old male pups

(fig. S4). At this age, the HCR and LCR lines had essentially

identical body and visceral fat weights, with a 25% greater VO2max in

the HCR relative to the LCR. The LCR pups showed 12% higher plasma

glucose (P < 0.001) and plasma triglyceride values (P < 0.04)

compared with the HCR pups. Thus, in our contrasting strains,

metabolic changes preceded the increase in body weight (fig. S4), a

result that is consistent with a role for hyperinsulinemia in weight

gain. Although mechanistic arguments have been put forward for either

pattern in humans, clinical studies have not resolved whether obesity

precedes or follows the development of insulin resistance in type 2

diabetes (18).

In summary, the present study demonstrated that selection for low

versus high intrinsic aerobic exercise capacity simultaneously

generated a differential load of metabolic and cardiovascular risk

factors. Rats with low aerobic capacity expressed low amounts of key

proteins required for mitochondrial function in skeletal muscle,

suggesting a mechanistic association. Although a direct cause-effect

relationship has not been proven, our observations support the notion

that impaired regulation of oxidative pathways in mitochondria may be

a common factor linking reduced total-body aerobic capacity to

cardiovascular and metabolic disease. This is in concert with

previous epidemiological and clinical studies (1–6, 19).

Cheer, Al Pater.