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1.  Association of the K153R polymorphism in the myostatin gene and extreme longevity 
Age  2013;35(6):2445-2454.
The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n = 156; 132 women, age range 100–111 years) and younger adults (controls, n = 384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1 %) than in controls (2.7 %) (P = 0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 (95 % confidence interval 1.67–7.28, P = 0.001), compared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, n = 79 (40 women), age range 100–104 years; younger controls, n = 316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6 %) compared to controls (3.0 %) (P = 0.004) was independently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity.
PMCID: PMC3825013  PMID: 23354683
Centenarians; MSTN; Genetics
2.  Exome sequencing of three cases of familial exceptional longevity 
Aging Cell  2014;13(6):1087-1090.
Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5–13) or within individual families (66–156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A,NRG1,RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.
PMCID: PMC4326919  PMID: 25116423
apolipoprotein B; centenarians; exome sequencing; longevity; rare variants
3.  McArdle disease does not affect skeletal muscle fibre type profiles in humans 
Biology Open  2014;3(12):1224-1227.
Patients suffering from glycogen storage disease V (McArdle disease) were shown to have higher surface electrical activity in their skeletal muscles when exercising at the same intensity as their healthy counterparts, indicating more muscle fibre recruitment. To explain this phenomenon, this study investigated whether muscle fibre type is shifted towards a predominance in type I fibres as a consequence of the disease. Muscle biopsies from the Biceps brachii (BB) (n = 9) or Vastus lateralis (VL) (n = 8) were collected over a 13-year period from male and female patients diagnosed with McArdle disease, analysed for myosin heavy chain (MHC) isoform content using SDS-PAGE, and compared to healthy controls (BB: n = 3; VL: n = 10). All three isoforms were expressed and no difference in isoform expression in VL was found between the McArdle patients and healthy controls (MHC I: 33±19% vs. 43±7%; MHC IIa: 52±9% vs. 40±7%; MHC IIx: 15±18% vs. 17±9%). Similarly, the BB isoform content was also not different between the two groups (MHC I: 33±14% vs. 30±11%; MHC IIa: 46±17% vs. 39±5%; MHC IIx: 21±13% vs. 31±14%). In conclusion, fibre type distribution does not seem to explain the higher surface EMG in McArdle patients. Future studies need to investigate muscle fibre size and contractility of McArdle patients.
PMCID: PMC4265760  PMID: 25432515
Myosin heavy chain; Glycogen storage disease V; Phosphorylase deficiency
4.  Prevalence of leisure-time sedentary behaviour and sociodemographic correlates: a cross-sectional study in Spanish adults 
BMC Public Health  2014;14(1):972.
Being physically inactive has been linked to a higher mortality and poorer quality of life. This cross-sectional study examines the prevalence of leisure-time sedentary behaviour in a population of Spanish adults and its correlates with several sociodemographic variables.
Data were collected from 1,330 subjects living in Madrid (age: 18-65 years, 51.6% women) by telephone interview. The sampling error was ±2.7% for a 95.5% confidence level. Leisure-time sedentary behaviour was assessed using the Global Physical Activity Questionnaire (version 2). Further factors examined were: country of birth, sex, age, civil state, education level, employment and economic status and physical activity of parents.
76.3% of the subjects interviewed reported a mostly sedentary leisure-time lifestyle. The remaining subjects (23.7%) reported a moderate to high level of physical activity, meeting minimum recommendations. Logistic regression adjusted for all variables identified the following population subsets as showing a greater risk of sedentary behaviour: women (odds ratio (OR) = 2.14; 95% confidence interval (CI): 1.64, 2.79), participants aged 41-50 years (OR = 1.64; 95%CI:1.05, 2.51), those with a middle economic status (OR = 1.48; 95% CI: 1.04, 2.10) or not providing information about their income (OR = 1.97; 95% CI: 1.05, 3.67), and those whose father (OR = 1.53; 95% CI: 1.13, 2.07) and/or mother (OR = 1.41; 95% CI: 1.01, 1.97) were never physically active during leisure-time.
The high prevalence of self-reported sedentary behaviour recorded suggests the need for public health policies targeted at increasing leisure-time physical activity levels. Our data identified several population subsets as priority candidates for possible interventions pursuing this goal.
PMCID: PMC4177254  PMID: 25239653
Physical activity; Sedentarism; Leisure-time; Adults; Madrid
5.  Protective effect of trehalose-loaded liposomes against UVB-induced photodamage in human keratinocytes 
Biomedical Reports  2014;2(5):755-759.
Trehalose, a naturally occurring non-reducing disaccharide, is known to act as a major protein stabilizer that can reduce ultraviolet B (UVB)-induced corneal damage when topically applied to the eye. However, due to the low skin permeability of trehalose, which makes the development of topical formulations difficult, its use as a skin photoprotective agent has been limited. Previous findings demonstrated that liposomes may significantly improve the intracellular delivery of trehalose. Therefore, the present study aimed to assess the protective effects of trehalose-loaded liposomes against UVB-induced photodamage using the immortalized human keratinocyte cell line, HaCaT. The effects were also compared to those of the common skin photoprotective compounds, including L-carnosine, L-(+)-ergothioneine, L-ascorbic acid and DL-α-tocopherol. The levels of cyclobutane pyrimidine dimers, 8-hydroxy-2′-deoxyguanosine and protein carbonylation in HaCaT cells were used as biological markers of UVB-induced damage. Compared to other compounds, trehalose-loaded liposomes showed the highest efficacy in reducing the levels of the three markers following UVB irradiation of HaCaT cells (all P<0.001 when compared to each of the four other photoprotective compounds). Therefore, these findings indicate that there may be a clinical application for trehalose-loaded liposomes, and further studies should be performed to assess the potential usefulness in skin photoprotection and the prevention of non-melanoma skin cancer.
PMCID: PMC4106593  PMID: 25054023
ultraviolet radiation; keratinocytes; trehalose; cyclobutane pyrimidine dimers; 8-hydroxy-2′-deoxyguanosine; protein carbonylation
6.  New Molecular Targets and Lifestyle Interventions to Delay Aging Sarcopenia 
PMCID: PMC4078253  PMID: 25071565
muscle atrophy; senescence factors; signaling pathways; frailty; pharmaceutical targets
7.  Feasibility of resistance training in adult McArdle patients: clinical outcomes and muscle strength and mass benefits 
We analyzed the effects of a 4-month resistance (weight lifting) training program followed by a 2-month detraining period in 7 adult McArdle patients (5 female) on: muscle mass (assessed by DXA), strength, serum creatine kinase (CK) activity and clinical severity. Adherence to training was ≥84% in all patients and no major contraindication or side effect was noted during the training or strength assessment sessions. The training program had a significant impact on total and lower extremities’ lean mass (P < 0.05 for the time effect), with mean values increasing with training by +855 g (95% confidence interval (CI): 30, 1679) and +547 g (95%CI: 116, 978), respectively, and significantly decreasing with detraining. Body fat showed no significant changes over the study period. Bench press and half-squat performance, expressed as the highest value of average muscle power (W) or force (N) in the concentric-repetition phase of both tests showed a consistent increase over the 4-month training period, and decreased with detraining. Yet muscle strength and power detraining values were significantly higher than pre-training values, indicating that a training effect was still present after detraining. Importantly, all the participants, with no exception, showed a clear gain in muscle strength after the 4-month training period, e.g., bench press: +52 W (95% CI: 13, 91); half-squat: +173 W (95% CI: 96, 251). No significant time effect (P > 0.05) was noted for baseline or post strength assessment values of serum CK activity, which remained essentially within the range reported in our laboratory for McArdle patients. All the patients changed to a lower severity class with training, such that none of them were in the highest disease severity class (3) after the intervention and, as such, they did not have fixed muscle weakness after training. Clinical improvements were retained, in all but one patient, after detraining, such that after detraining all patients were classed as class 1 for disease severity.
PMCID: PMC4263173  PMID: 25566067
rhabdomyolysis; muscle atrophy; muscle weakness; glycogenosis; weight lifting; exercise is medicine
8.  Are centenarians genetically predisposed to lower disease risk? 
Age  2011;34(5):1269-1283.
Our study purpose was to compare a disease-related polygenic profile that combined a total of 62 genetic variants among (i) people reaching exceptional longevity, i.e., centenarians (n = 54, 100–108 years, 48 women) and (ii) ethnically matched healthy controls (n = 87, 19–43 years, 47 women). We computed a ‘global’ genotype score (GS) for 62 genetic variants (mutations/polymorphisms) related to cardiometabolic diseases, cancer or exceptional longevity, and also specific GS for main disease categories (cardiometabolic risk and cancer risk, including 36 and 24 genetic variations, respectively) and for exceptional longevity (7 genetic variants). The ‘global’ GS was similar among groups (centenarians: 31.0 ± 0.6; controls 32.0 ± 0.5, P = 0.263). We observed that the GS for hypertension, cancer (global risk), and other types of cancer was lower in the centenarians group compared with the control group (all P < 0.05), yet the difference became non significant after adjusting for sex. We observed significant between-group differences in the frequency of GSTT1 and GSTM1 (presence/absence) genotypes after adjusting for multiple comparisons. The likelihood of having the GSTT1 low-risk (functional) allele was higher in centenarians (odds ratio [OR] 5.005; 95% confidence interval [CI], 1.810–13.839), whereas the likelihood of having the GSTMI low-risk (functional) allele was similar in both groups (OR 1.295; 95% CI, 0.868 –1.931). In conclusion, we found preliminary evidence that Spanish centenarians have a lower genetic predisposition for cancer risk. The wild-type (i.e., functional) genotype of GSTT1, which is associated with lower cancer risk, might be associated with exceptional longevity, yet further studies with larger sample sizes must confirm these findings.
PMCID: PMC3448993  PMID: 21894447
Centenarians; Genetics; Exceptional longevity; Ageing
9.  The FTO A/T Polymorphism and Elite Athletic Performance: A Study Involving Three Groups of European Athletes 
PLoS ONE  2013;8(4):e60570.
The FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism.
Subjects and Methods
A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport (endurance athletes, n = 266 vs. sprint/power athletes, n = 285) as well as by level of competition (elite-level vs. national-level). The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level.
There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status (endurance athletes, sprint/power athletes or control participants). These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition (elite-level vs. national-level).
The FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics.
PMCID: PMC3616005  PMID: 23573268
10.  Are mitochondrial haplogroups associated with extreme longevity? A study on a Spanish cohort 
Age  2011;34(1):227-233.
Mitochondrial haplogroups could influence individual susceptibility to mitochondrial DNA (mtDNA) damage, and human longevity, as indicated by previous studies with Caucasian (European) or Asian cohorts. Here, we compared the frequency of mtDNA haplogroups in a group of Spanish (Caucasian) centenarians (n = 65, aged 100–108 years, 58 women, most from the central part of Spain) and a group of healthy young adults (n = 138, 62 women, aged 20–40 years) of the same ethnic origin. We did not find significant differences between centenarians and the control group (P > 0.2). Only two centenarians (both women) had the haplogroup J, which hampered comparison with the control group (n = 15, five women). Our data confirm that the potential effects of mitochondrial haplogroups on human longevity might be population/geographic specific, with important differences between studies (notably, with regard to the previously reported potential benefit brought about by the haplogroup J) arising from the different living environment and ethnic background of the study cohorts.
PMCID: PMC3260354  PMID: 21274636
Genetics; Mitochondria; Centenarians
11.  The ACTN3 R577X Polymorphism across Three Groups of Elite Male European Athletes 
PLoS ONE  2012;7(8):e43132.
The ACTN3 R577X polymorphism (rs1815739) is a strong candidate to influence elite athletic performance. Yet, controversy exists in the literature owing to between-studies differences in the ethnic background and sample size of the cohorts, the latter being usually low, which makes comparisons difficult. In this case:control genetic study we determined the association between elite athletic status and the ACTN3 R577X polymorphism within three cohorts of European Caucasian men, i.e. Spanish, Polish and Russian [633 cases (278 elite endurance and 355 power athletes), and 808 non-athletic controls]. The odds ratio (OR) of a power athlete harbouring the XX versus the RR genotype compared with sedentary controls was 0.54 [95% confidence interval (CI): 0.34–0.48; P = 0.006]. We also observed that the OR of an endurance athlete having the XX versus the RR genotype compared with power athletes was 1.88 (95%CI: 1.07–3.31; P = 0.028). In endurance athletes, the OR of a “world-class” competitor having the XX genotype versus the RR+RX genotype was 3.74 (95%CI: 1.08–12.94; P = 0.038) compared with those of a lower (“national”) competition level. No association (P>0.1) was noted between the ACTN3 R577X polymorphism and competition level (world-class versus national-level) in power athletes. Our data provide comprehensive support for the influence of the ACTN3 R577X polymorphism on elite athletic performance.
PMCID: PMC3420864  PMID: 22916217
12.  Acyl Coenzyme A Synthetase Long-Chain 1 (ACSL1) Gene Polymorphism (rs6552828) and Elite Endurance Athletic Status: A Replication Study 
PLoS ONE  2012;7(7):e41268.
The aim of this study was to determine the association between the rs6552828 polymorphism in acyl coenzyme A synthetase (ACSL1) and elite endurance athletic status. We studied 82 Caucasian (Spanish) World/Olympic-class endurance male athletes, and a group of sex and ethnically matched healthy young adults (controls, n = 197). The analyses were replicated in a cohort of a different ethnic origin (Chinese of the Han ethnic group), composed of elite endurance athletes (runners) [cases, n = 241 (128 male)] and healthy sedentary adults [controls, n = 504 (267 male)]. In the Spanish cohort, genotype (P = 0.591) and minor allele (A) frequencies were similar in cases and controls (P = 0.978). In the Chinese cohort, genotype (P = 0.973) and minor allele (G) frequencies were comparable in female endurance athletes and sedentary controls (P = 0.881), whereas in males the frequency of the G allele was higher in endurance athletes (0.40) compared with their controls (0.32, P = 0.040). The odds ratio (95%CI) for an elite endurance Chinese athlete to carry the G allele compared with ethnically matched controls was 1.381 (1.015–1.880) (P-value = 0.04). Our findings suggest that the ACSL1 gene polymorphism rs6552828 is not associated with elite endurance athletic status in Caucasians, yet a marginal association seems to exist for the Chinese (Han) male population.
PMCID: PMC3400600  PMID: 22829935
13.  Activity in GEriatric acute CARe (AGECAR): rationale, design and methods 
BMC Geriatrics  2012;12:28.
The Activity in GEriatric acute CARe (AGECAR) is a randomised control trial to assess the effectiveness of an intrahospital strength and walk program during short hospital stays for improving functional capacity of patients aged 75 years or older.
Patients aged 75 years or older admitted for a short hospital stay (≤14 days) will be randomly assigned to either a usual care (control) group or an intervention (training) group. Participants allocated in the usual care group will receive normal hospital care and participants allocated in the intervention group will perform multiple sessions per day of lower limb strength training (standing from a seated position) and walking (10 min bouts) while hospitalized. The primary outcome to be assessed pre and post of the hospital stay will be functional capacity, using the Short Physical Performance Battery (SPPB), and time to walk 10 meters. Besides length of hospitalization, the secondary outcomes that will also be assessed at hospital admission and discharge will be pulmonary ventilation (forced expiratory volume in one second, FEV1) and peripheral oxygen saturation. The secondary outcomes that will be assessed by telephone interview three months after discharge will be mortality, number of falls since discharge, and ability to cope with activities of daily living (ADLs, using the Katz ADL score and Barthel ADL index).
Results will help to better understand the potential of regular physical activity during a short hospital stay for improving functional capacity in old patients. The increase in life expectancy has resulted in a large segment of the population being over 75 years of age and an increase in hospitalization of this same age group. This calls attention to health care systems and public health policymakers to focus on promoting methods to improve the functional capacity of this population.
Trial registration ID: NCT01374893.
PMCID: PMC3420239  PMID: 22682063
Randomised controlled trial; Ageing; Hospitalisation; Elderly; Intrahospital exercise; Functional capacity
14.  A Transcriptomic Approach to Search for Novel Phenotypic Regulators in McArdle Disease 
PLoS ONE  2012;7(2):e31718.
McArdle disease is caused by lack of glycogen phosphorylase (GP) activity in skeletal muscle. Patients experience exercise intolerance, presenting as early fatigue and contractures. In this study, we investigated the effects produced by a lack of GP on several genes and proteins of skeletal muscle in McArdle patients. Muscle tissue of 35 patients and 7 healthy controls were used to identify abnormalities in the patients' transcriptomic profile using low-density arrays. Gene expression was analyzed for the influence of variables such as sex and clinical severity. Differences in protein expression were studied by immunoblotting and 2D electrophoresis analysis, and protein complexes were examined by two-dimensional, blue native gel electrophoresis (BN-PAGE). A number of genes including those encoding acetyl-coA carboxylase beta, m-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1), were found to be downregulated in patients. Specifically, compared to controls, GS and SERCA1 proteins were reduced by 50% and 75% respectively; also, unphosphorylated GS and SERCA1 were highly downregulated. On BN-PAGE analysis, GP was present with GS in two muscle protein complexes. Our findings revealed some issues that could be important in understanding the physiological consequences of McArdle disease: (i) SERCA1 downregulation in patients could result in impaired calcium transport in type II (fast-twitch) muscle fibers, leading to early fatigability during exercise tasks involving type II fibers (which mostly use glycolytic metabolism), i.e. isometric exercise, lifting weights or intense dynamic exercise (stair climbing, bicycling, walking at a very brisk pace), (ii) GP and GS were found together in two protein complexes, which suggests a new regulatory mechanism in the activity of these glycogen enzymes.
PMCID: PMC3276513  PMID: 22347505
15.  Health-related quality of life of Spanish children with cystic fibrosis 
Quality of Life Research  2012;21(10):1837-1845.
To investigate (1) the contributions of sex, age, nutritional status- and physical-fitness-related variables on health-related quality of life (HRQOL) in Spanish children with cystic fibrosis, and (2) the agreement on HRQOL between children and their parents.
In 28 children aged 6–17 years, body mass index percentile, percentage body fat, physical activity, pulmonary function, cardiorespiratory fitness, functional mobility, and dynamic muscle strength were determined using objective measures. HRQOL was measured using the revised version of the cystic fibrosis questionnaire. Simple and multiple linear regression analyses were performed to determine the variables associated with HRQOL. To assess the agreement on HRQOL between children and parents, intra-class correlation coefficients (ICCs) were calculated.
Girls reported worse emotional functioning, a higher treatment burden, and more respiratory problems than boys. Greater functional mobility appeared associated with a less favourable body image and more eating disturbances. Agreement on HRQOL between children and parents was good to excellent, except for the domain of treatment burden.
Sex and age were stronger predictors of HRQOL than nutritional status- or physical-fitness-related variables. Children reported a lower treatment burden than their parents perceived them to have.
PMCID: PMC3496548  PMID: 22219170
Cystic fibrosis; Quality of life; Children; Parents; Physical fitness; Nutritional status
16.  ‘Smoking Genes’: A Genetic Association Study 
PLoS ONE  2011;6(10):e26668.
Some controversy exists on the specific genetic variants that are associated with nicotine dependence and smoking-related phenotypes. The purpose of this study was to analyse the association of smoking status and smoking-related phenotypes (included nicotine dependence) with 17 candidate genetic variants: CYP2A6*1×2, CYP2A6*2 (1799T>A) [rs1801272], CYP2A6*9 (−48T>G) [rs28399433], CYP2A6*12, CYP2A13*2 (3375C>T) [rs8192789], CYP2A13*3 (7520C>G), CYP2A13*4 (579G>A), CYP2A13*7 (578C>T) [rs72552266], CYP2B6*4 (785A>G), CYP2B6*9 (516G>T), CHRNA3 546C>T [rs578776], CHRNA5 1192G>A [rs16969968], CNR1 3764C>G [rs6928499], DRD2-ANKK1 2137G>A (Taq1A) [rs1800497], 5HTT LPR, HTR2A −1438A>G [rs6311] and OPRM1 118A>G [rs1799971]. We studied the genotypes of the aforementioned polymorphisms in a cohort of Spanish smokers (cases, N = 126) and ethnically matched never smokers (controls, N = 80). The results showed significant between-group differences for CYP2A6*2 and CYP2A6*12 (both P<0.001). Compared with carriers of variant alleles, the odds ratio (OR) for being a non-smoker in individuals with the wild-type genotype of CYP2A6*12 and DRD2-ANKK1 2137G>A (Taq1A) polymorphisms was 3.60 (95%CI: 1.75, 7.44) and 2.63 (95%CI: 1.41, 4.89) respectively. Compared with the wild-type genotype, the OR for being a non-smoker in carriers of the minor CYP2A6*2 allele was 1.80 (95%CI: 1.24, 2.65). We found a significant genotype effect (all P≤0.017) for the following smoking-related phenotypes: (i) cigarettes smoked per day and CYP2A13*3; (ii) pack years smoked and CYP2A6*2, CYP2A6*1×2, CYP2A13*7, CYP2B6*4 and DRD2-ANKK1 2137G>A (Taq1A); (iii) nicotine dependence (assessed with the Fagestrom test) and CYP2A6*9. Overall, our results suggest that genetic variants potentially involved in nicotine metabolization (mainly, CYP2A6 polymorphisms) are those showing the strongest association with smoking-related phenotypes, as opposed to genetic variants influencing the brain effects of nicotine, e.g., through nicotinic acetylcholine (CHRNA5), serotoninergic (HTR2A), opioid (OPRM1) or cannabinoid receptors (CNR1).
PMCID: PMC3202555  PMID: 22046326
17.  The K153R variant in the myostatin gene and sarcopenia at the end of the human lifespan 
Age  2010;32(3):405-409.
We studied the A55T, E164K, I225T, K153R and P198A variants in the myostatin (GDF8) gene, muscle strength and mass, and physical function during daily living in 41 nonagenarians [33 women, age range, 90, 97]. No participant carried a mutant allele of the aforementioned variants, except three participants (all women), who carried the R allele of the K153R polymorphism, with one of them (woman aged 96 years) being homozygous. Overall, in KR women muscle phenotype values (1RM leg press and estimated muscle mass) were low-to-normal compared to the whole group (∼25th–50th percentile), and their functional capacity (Barthel and Tinetti tests) was normal. In the woman bearing the RR genotype, values of muscle mass and functional capacity were below the 25th percentile. She is the first RR Caucasian whose phenotype has been characterised specifically. In summary, heterozygosity for the GDF8 K153R polymorphism does not seem to exert a negative influence on the muscle phenotypes of women who are at the end of the human lifespan, yet homozygosity might do so. More research on larger cohorts of nonagenarians is needed to corroborate the present findings.
PMCID: PMC2926851  PMID: 20640547
Activities of daily living; GDF-8; Muscle strength; Nonagenarians
18.  Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism 
PLoS ONE  2011;6(3):e17558.
Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition.
PMCID: PMC3048287  PMID: 21407828
19.  C34T mutation of the AMPD1 gene in an elite white runner 
BMJ Case Reports  2009;2009:bcr07.2008.0535.
The case is reported of an elite, male, white endurance runner (28 years of age), who is one of the best non-African runners in the world despite carrying the C34T mutation in the gene (AMPD1) that encodes the skeletal muscle specific isoform of AMP deaminase, an enzyme important in muscle metabolism. The frequency of the mutant allele in sedentary white people is 8–11%. Previous research has shown that this mutation, at least in homozygotes, can impair the exercise capacity of untrained people and their trainability. The maximum oxygen uptake (VO2MAX) of the study subject was exceptionally high (83.6 mlO2/kg/min), whereas his ammonia and lactate concentrations at high submaximal running speeds were lower than those of other world class runners who are not carriers of the mutation. The partial metabolic deficiency of the study subject is possibly compensated for by his exceptionally favourable anthropometric characteristics (body mass index 18.2 kg/m2).
PMCID: PMC3029538  PMID: 21686757
20.  The K153R Polymorphism in the Myostatin Gene and Muscle Power Phenotypes in Young, Non-Athletic Men 
PLoS ONE  2011;6(1):e16323.
The Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes. We examined the association between the MSTN K153R polymorphism and ‘explosive’ leg power, assessed during sprint (30 m) and stationary jumping tests [squat (SJ) and counter-movement jumps (CMJ)] in non-athletic young adults (University students) [n = 281 (214 men); age: 21–32 years]. We also genotyped the MSTN exonic variants E164K (rs35781413), I225T, and P198A, yet no subject carried any of these variant MSTN alleles. As for the K153R polymorphism, we found only one woman with the KR genotype; thus, we presented the results only for men. The results of a one-way ANCOVA (with age, weight and height entered as covariates) showed that men with the KR genotype (n = 15) had a worse performance in vertical jumps compared with those with the KK genotype [SJ: vertical displacement of center of gravity (CG) of 35.17±1.42 vs. 39.06±0.39 cm, respectively, P = 0.009; CMJ: vertical displacement of CG of 36.44±1.50 vs. 40.63±0.41 cm, respectively, P = 0.008]. The results persisted after adjusting for multiple comparisons according to Bonferroni. Performance in 30 m sprint tests did however not differ by K153R genotypes. In summary, the MSTN K153R polymorphism is associated with the ability to produce ‘peak’ power during muscle contractions, as assessed with vertical jump tests, in young non-athletic men. Although more research is still needed, this genetic variation is among the numerous candidates to explain, alone or in combination with other polymorphisms, individual variations in muscle phenotypes.
PMCID: PMC3024427  PMID: 21283721
21.  Expression of Glycogen Phosphorylase Isoforms in Cultured Muscle from Patients with McArdle's Disease Carrying the p.R771PfsX33 PYGM Mutation 
PLoS ONE  2010;5(10):e13164.
Mutations in the PYGM gene encoding skeletal muscle glycogen phosphorylase (GP) cause a metabolic disorder known as McArdle's disease. Previous studies in muscle biopsies and cultured muscle cells from McArdle patients have shown that PYGM mutations abolish GP activity in skeletal muscle, but that the enzyme activity reappears when muscle cells are in culture. The identification of the GP isoenzyme that accounts for this activity remains controversial.
Methodology/Principal Findings
In this study we present two related patients harbouring a novel PYGM mutation, p.R771PfsX33. In the patients' skeletal muscle biopsies, PYGM mRNA levels were ∼60% lower than those observed in two matched healthy controls; biochemical analysis of a patient muscle biopsy resulted in undetectable GP protein and GP activity. A strong reduction of the PYGM mRNA was observed in cultured muscle cells from patients and controls, as compared to the levels observed in muscle tissue. In cultured cells, PYGM mRNA levels were negligible regardless of the differentiation stage. After a 12 day period of differentiation similar expression of the brain and liver isoforms were observed at the mRNA level in cells from patients and controls. Total GP activity (measured with AMP) was not different either; however, the active GP activity and immunoreactive GP protein levels were lower in patients' cell cultures. GP immunoreactivity was mainly due to brain and liver GP but muscle GP seemed to be responsible for the differences.
These results indicate that in both patients' and controls' cell cultures, unlike in skeletal muscle tissue, most of the protein and GP activities result from the expression of brain GP and liver GP genes, although there is still some activity resulting from the expression of the muscle GP gene. More research is necessary to clarify the differential mechanisms of metabolic adaptations that McArdle cultures undergo in vitro.
PMCID: PMC2950139  PMID: 20957198
22.  Citius and longius (faster and longer) with no α‐actinin‐3 in skeletal muscles? 
The muscle protein α‐actinin‐3 (ACTN3) is normally thought to be expressed in type II muscle fibres and to be necessary for high‐power, high‐velocity muscle contractions, such as those typically seen in speed/power athletes. The authors report the case of a Spanish elite long jumper (two times Olympian, personal best of 8.26 m) whose genotype for the ACTN3 gene is 577XX (ACTN3 deficient). These data suggest that there might be notable exceptions to the concept that ACTN3 is the “gene for speed”.
PMCID: PMC2465381  PMID: 17289854
23.  Health enhancing strength training in nonagenarians (STRONG): rationale, design and methods 
BMC Public Health  2009;9:152.
The Health Enhancing Strength Training in Nonagenarians (STRONG) is a randomised control trial to assess the effectiveness of an aerobic and strength training program for improving muscle strength, functional capacity and quality of life in nonagenarians.
Sixty (51 women) nonagenarians (age range: 90–102 years) who live in a geriatric nursing home will be randomly assigned to either a usual care (control) group (n = 30) or an intervention (training) group (n = 30). Participants allocated in the usual care group will receive general physical activity guidelines and participants allocated in the intervention group will also enrol in three weekly non-consecutive individualized training sessions (~45–50 min each) during 8 weeks. The exercise program will consist of muscular strength [with a special focus on leg press at 30% (start of the program) to 70% 1 repetition maximum (end)] and aerobic exercises (cycle-ergometry during 3–5 to 15 minutes at 12–14 points in the rate of perceived exertion scale).
Results from STRONG will help to better understand the potential of regular physical activity for improving the well-being of the oldest population groups.
The increase in life expectancy together with the dramatic decrease in birth rates in industrialized countries calls the attention to health care systems and public health policymakers to focus attention on promoting healthy lifestyle in the highest sector of the population pyramid. Our study attempts to improve functional capacity and QOL of nonagenarians by implementing an individualised aerobic and strength training program in a geriatric residential care. Results from STRONG will help to better understand the potential of regular physical activity for improving the well being even in persons aged 90 years or over.
Trail Registration ID: NCT00848978
PMCID: PMC2693136  PMID: 19470176
24.  How Do Humans Control Physiological Strain during Strenuous Endurance Exercise? 
PLoS ONE  2008;3(8):e2943.
Distance running performance is a viable model of human locomotion.
Methodology/Principal Findings
To evaluate the physiologic strain during competitions ranging from 5–100 km, we evaluated heart rate (HR) records of competitive runners (n = 211). We found evidence that: 1) physiologic strain (% of maximum HR (%HRmax)) increased in proportional manner relative to distance completed, and was regulated by variations in running pace; 2) the %HRmax achieved decreased with relative distance; 3) slower runners had similar %HRmax response within a racing distance compared to faster runners, and despite differences in pace, the profile of %HRmax during a race was very similar in runners of differing ability; and 4) in cases where there was a discontinuity in the running performance, there was evidence that physiologic effort was maintained for some time even after the pace had decreased.
The overall results suggest that athletes are actively regulating their relative physiologic strain during competition, although there is evidence of poor regulation in the case of competitive failures.
PMCID: PMC2491903  PMID: 18698405

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