Roger P. Farrar

Endurance training effects on striatal D2 dopamine receptor binding and striatal dopamine metabolites in presenescent older rats

Endurance training is associated with higher binding of 3H-spiperone to striatal D2 dopamine receptors of rats sacrificed 48 h following the last exercise bout (Gilliam et al. 1984). In the present study we investigated the effects of endurance training in presenescent older rats on the relationship between steady-state levels of DA and its metabolites in striatum versus the affinity and density of striatal D2 DA receptors. Citrate synthase activity of the gastrocnemius-plantaris muscle was 29.06±2.27 μmole/g wet wt in 21-month-old trained rats versus 22.88±1.13 μmole/g wet wt in 21-month-old untrained animals.DOPAC levels and DOPAC/DA ratios were greater in the old controls. Endurance training was associated with lower DOPAC levels in the 21-month-old animals. Thus, endurance training may postpone selectively changes in DA metabolism over a portion of the lifespan.As expected, the number of D2 DA binding sites was reduced with age (6 months Bmax:429±21 fmoles/mg protein; 21 months:355±20) with no change in affinity. The Bmax of old runners was significantly higher (457 ± 38 fmoles/mg protein) than that of old controls. Thus, endurance training appears to exert a protective effect on D2 dopamine receptors during the lifespan. Taken together, the present results suggest that there may be a possible reciprocal relationship between changes in DA metabolites and DA binding as a function of exercise in presenescent older rats, and that endurance training may decelerate the effects of age both on nigrostriatal dopamine neurons and on striatal D2 dopamine receptors during a portion of the lifespan.

The effects of exercise training on [3H]-spiperone binding in rat striatum

Thirty male Sprague-Dawley rats 100 days of age were divided into three groups: interval trained, endurance trained, and pair-weighted controls. Both trained groups ran up to one hour per day, 6 days per week for 12 weeks. The interval trained group ran up to 20 repeat intervals at 54 meters per minute for 30 seconds, while the endurance trained group ran at 27 meters per minute for 60 minutes. The animals were sacrificed, and the effects of aerobic training were documented by measuring cytochrome oxidase activity in the mixed quadriceps muscles. The cytochrome oxidase activity of the interval and endurance trained groups increased 49%, and 31% respectively, above the control group. [3H]-spiperone was used to label dopamine receptors in the striatum. The endurance group was not significantly different from the interval group in [3H]-spiperone receptor binding, so the two exercise groups were combined to form one group of runners. The runners had significantly higher [3H]-spiperone receptor binding than the controls, F(1,26) = 4.87, p less than 0.05. The mean and standard error for receptor binding was 89 +/- 13 fmoles/mg protein for the runners and 60 +/- 5 fmoles/mg protein for the controls.

Proteomic analysis of rat soleus muscle undergoing hindlimb suspension‐induced atrophy and reweighting hypertrophy

A proteomic analysis was performed comparing normal rat soleus muscle to soleus muscle that had undergone either 0.5, 1, 2, 4, 7, 10 and 14 days of hindlimb suspension‐induced atrophy or hindlimb suspension‐induced atrophied soleus muscle that had undergone 1 hour, 8 hour, 1 day, 2 day, 4 day and 7 days of reweighting‐induced hypertrophy. Muscle mass measurements demonstrated continual loss of soleus mass occurred throughout the 21 days of hindlimb suspension; following reweighting, atrophied soleus muscle mass increased dramatically between 8 hours and 1 day post reweighting. Proteomic analysis of normal and atrophied soleus muscle demonstrated statistically significant changes in the relative levels of 29 soleus proteins. Reweighting following atrophy demonstrated statistically significant changes in the relative levels of 15 soleus proteins. Protein identification using mass spectrometry was attempted for all differentially regulated proteins from both atrophied and hypertrophied soleus muscle. Five differentially regulated proteins from the hindlimb suspended atrophied soleus muscle were identified while five proteins were identified in the reweighting‐induced hypertrophied soleus muscles. The identified proteins could be generally grouped together as metabolic proteins, chaperone proteins and contractile apparatus proteins. Together these data demonstrate that coordinated temporally regulated changes in the skeletal muscle proteome occur during disuse‐induced soleus muscle atrophy and reweighting hypertrophy.

Serum IGF-I-deficiency does not prevent compensatory skeletal muscle hypertrophy in resistance exercise

The involvement of circulating insulin-like growth factor-I (IGF-I) in the skeletal muscle response to resistance exercise is currently unclear. To address this, we utilized the liver IGF-I-deficient (LID) mouse model, in which the igf1 gene has been disrupted in the hepatocytes, resulting in ~80% reduction in serum IGF-I. Twelve- to 13-month-old male LID and control (L/L) mice were subjected to 16 weeks of resistance training. Resistance exercise resulted in equal strength gains in both L/L and LID mice. Basal IGF-I mRNA levels were greater in LID muscles than in L/L, and exercise increased IGF-I mRNA in quadriceps, gastrocnemius, and plantaris muscles. LID mice had elevated tyrosine phosphorylation of IGF-IR and Stat5b, the latter possibly reflective of increased serum GH. Tyrosine phosphorylation of IGF-IR was increased, while phospho-Stat5b was reduced after resistance training of both wild-type and LID mice. These data suggest that: 1) performance and recovery in response to resistance training is normal even when there is severe deficiency of circulating IGF-I; and 2) upregulation of local IGF-I may be involved in the compensatory growth of muscle that occurs in response to resistance training. Decreased levels of p-Stat5b in exercised mice suggests that the upregulation of local IGF-I gene expression in response to exercise may be GH-independent.

Reductions in serum IGF-1 during aging impair health span.

In lower or simple species, such as worms and flies, disruption of the insulin‐like growth factor (IGF)‐1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF‐1 levels in serum and tissues and can modulate lifespan via/or independent of IGF‐1. Rodent models, where the GH/IGF‐1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF‐1 levels are high throughout life, in humans, serum IGF‐1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF‐1 axis are unable to clearly distinguish between developmental and age‐related effects of GH/IGF‐1 on health. To overcome this caveat, we developed an inducible liver IGF‐1‐deficient (iLID) mouse that allows temporal control of serum IGF‐1. Deletion of liver Igf ‐1 gene at one year of age reduced serum IGF‐1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF‐1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF‐1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF‐1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.

Stress Reactivity in Fire Fighters: An Exercise Intervention

This experiment was designed to investigate the efficacy of 16 weeks of exercise training as an intervention to reduce the psychophysiological response of fire fighters to psychological stress. Fifty-three members of the Austin Fire Department (AFD) were recruited as participants and were randomly assigned to either exercise on a rowing ergometer or to continue their present modes of exercise training. Psychological stress was induced by a computerized version of the AFD Strategy and Tactics Drill (STD), in which participants responded to a simulated fire scene. Participants completed the STD prior to and following the exercise intervention. Prior to training, the groups did not differ in their cardiovascular response to the STD. Significant group differences were observed after training, in which exercise-trained participants reacted with significantly lower pulse and mean arterial pressure than their counterparts in the control condition. Exercise participants also reported significantly less stress-related state anxiety and negative affect. Exercise training appears to be a useful intervention to reduce the response to fire-related psychological stress in fire fighters.

Chronic ethanol treatment uncouples striatal calcium entry and endogenous dopamine release

Chronic ethanol treatment resulted in a marked reduction in the release of dopamine from striatal synaptosomes in response to depolarization. Calcium entry into the same synaptosomal preparations was not altered. Calculation of the ratio of calcium entry vs dopamine release showed that, under control conditions, approximately 15 calcium ions were required to cause the release of 1 dopamine molecule. Chronic ethanol treatment increased this ratio to more than 80:1, suggesting that chronic ethanol administration altered the coupling between calcium entry and dopamine release. Addition of ethanol in vitro to synaptosomes isolated from chronic ethanol-treated rats returned this ratio to approximately 20:1. These results suggest that chronic ethanol treatment results in dependence which is reflected biochemically in striatum through changes in the coupling between voltage-dependent calcium entry into nerve endings and subsequent neurotransmitter release.

Effect of physical activity on hippocampal high affinity choline uptake and muscarinic binding : a comparison between young and old F344 rats

Normal aging has been associated with a progressive decline in hippocampal cholinergic function. In the present study, specific markers of hippocampal cholinergic function, high-affinity choline uptake (HACU) and muscarinic quinuclidinylbenzilate (QNB) binding, were shown to be altered by endurance training (6 months of treadmill running, 5 days/week, 30 min/day). HACU and QNB binding were determined in synaptosomes of endurance trained F344 rats and their age-matched sedentary controls. Comparison of synaptosomes of sedentary rats ages 3 months, 12 months and 25 months (distinguished in this paper as young (Y), middle age (MA) and old (O), respectively) showed maximum HACU at 12 months and subsequent reduction in HACU and QNB binding at 25 months (P less than 0.05). This decline at 25 months is consistent with previous reports of an age-related decline in cholinergic function. Endurance trained rats (trained from 6 months to 12 months of age) showed a reduction (P less than 0.02) in HACU and an increase (P less than 0.05) in QNB binding compared to their age-matched sedentary controls whereas endurance trained rats (trained from 19 months to 25 months of age) showed no significant difference in either parameter from their age-matched sedentary controls. From these results, it appears that while both training and normal aging reduce HACU, the reductions may be different in presynaptic mechanism and postsynaptic consequence.

Controlled release of IGF‐I from a biodegradable matrix improves functional recovery of skeletal muscle from ischemia/reperfusion

Ischemia/reperfusion (I/R) injury is a considerable insult to skeletal muscle, often resulting in prolonged functional deficits. The purpose of the current study was to evaluate the controlled release of the pro‐regenerative growth factor, insulin‐like growth factor‐I (IGF‐I), from a biodegradable polyethylene glycol (PEG)ylated fibrin gel matrix and the subsequent recovery of skeletal muscle from I/R. To accomplish this, the hind limbs of male Sprague–Dawley rats were subjected to 2‐h tourniquet‐induced I/R then treated with saline, bolus IGF‐I (bIGF), PEGylated fibrin gel (PEG‐Fib), or IGF‐I conjugated PEGylated fibrin gel (PEG‐Fib‐IGF). Functional and histological evaluations were performed following 14 days of reperfusion, and muscles from 4‐day reperfusion animals were analyzed by Western blotting and histological assessments. There was no difference in functional recovery between saline, bIGF, or PEG‐Fib groups. However, PEG‐Fib‐IGF treatment resulted in significant improvement of muscle function and structure, as observed histologically. Activation of the PI3K/Akt pathway was significantly elevated in PEG‐Fib‐IGF muscles, compared to PEG‐Fib treatment, at 4 days of reperfusion, suggesting involvement of the pathway PI3K/Akt as a mediator of the improved function. Surprisingly, myoblast activity was not evident as a result of PEG‐Fib‐IGF treatment. Taken together, these data give evidence for a protective role for the delivered IGF. These results indicate that PEG‐Fib‐IGF is a viable therapeutic technique in the treatment of skeletal muscle I/R injury. Biotechnol. Bioeng. 2012; 109:1051–1059.

Prediction of Aerobic Capacity in Firefighters Using Submaximal Treadmill and Stairmill Protocols

Tierney, MT, Lenar, D, Stanforth, PR, Craig, JN, and Farrar, RP. Prediction of aerobic capacity in firefighters using submaximal treadmill and stairmill protocols. J Strength Cond Res 24(3): 757-764, 2010-Accurate assessments of aerobic capacity are essential to ensuring the health and well-being of firefighters, given their arduous and stressful working conditions. The use of a submaximal protocol, if proven accurate, addresses concerns such as administrative cost, time, and ease of test performance. The purposes of this study were to develop and validate graded submaximal and maximal stairmill protocols and to develop accurate maximal and submaximal equations to predict peak &OV0312;o2 using both the stairmill and Gerkin treadmill protocols. Fifty-four subjects, men (36.3 ± 5.6 years) and women (36.4 ± 6.3 years), performed maximal graded exercise tests using both the stairmill and Gerkin treadmill protocols. Significant predictors of peak &OV0312;o2 included body mass index, time to completion for maximal protocols, and time to 85% of predicted maximal heart rate for submaximal protocols. Maximal prediction equations were more accurate on both the treadmill (R2 = 0.654, standard error of the estimate [SEE] = 3.73 ml·kg−1·min−1) and stairmill (R2 = 0.816, SEE = 2.89 ml·kg−1·min−1) than developed submaximal prediction equations for both the treadmill (R2 = 0.325, SEE = 5.20 ml·kg−1·min−1) and stairmill (R2 = 0.480, SEE = 4.85 ml·kg−1·min−1). Both of the newly developed submaximal prediction equations more accurately predict peak &OV0312;o2 than the current Gerkin equation. In summary, we support the use of both the stairmill and treadmill as a means for aerobic assessment in this population. The use of the developed submaximal prediction equations should lead to a reduced cost and time of assessment; however, direct measurement of maximal oxygen consumption remains the better alternative.