The present study aims to explore the potential influence of leucocyte telomere length (LTL) on both a single indicator and a composite construct of physical functioning in a large European population of elderly men and women across diverse geographical locations. A total of 1,221 adults (65-79 years) were recruited from five European countries within the framework of NU-AGE study. The physical functioning construct was based on the 36-item Short Form Health Survey. Handgrip strength was used as a single indicator of muscle function and LTL was assessed using quantitative real-time PCR. Women had significantly longer (p < 0.05) LTL than men. Participants in Poland had significantly shorter LTL than in the other study centers, whereas participants in the Netherlands had significantly longer LTL than most of the other centers (p < 0.01). An analysis of LTL as a continuous outcome against physical functioning by using linear models revealed inconsistent findings. In contrast, based on an analysis of contrasting telomere lengths (first vs. fifth quintile of LTL), a significant odds ratio (OR) of 1.7 (95% CI: 1.1 -2.6; p < 0.05) of having functional limitation was observed in those belonging to the first LTL quintile compared to the fifth. Interestingly, having the shortest LTL was still related to a higher likelihood of having physical limitation when compared to all remaining quintiles (OR: 1.5, 95% CI: 1.1 -2.1; p < 0.05), even after adjustment by study center, age, sex, and overweight status. Collectively, our findings suggest that short LTL is an independent risk factor that accounts for functional decline in elderly European populations. The influence of LTL on functional limitation seems driven by the detrimental effect of having short telomeres rather than reflecting a linear dose-response relationship.

Estrogen-based hormone replacement therapy (HRT) may be associated with deceleration of cellular aging. We investigated whether long-term HRT has effects on leukocyte (LTL) or mean and minimum skeletal muscle telomere length (SMTL) in a design that controls for genotype and childhood environment. Associations between telomeres, body composition, and physical performance were also examined. Eleven monozygotic twin pairs (age 57.6 ± 1.8 years) discordant for HRT were studied. Mean duration of HRT use was 7.3 ± 3.7 years in the user sister, while their co-twins had never used HRT. LTL was measured by qPCR and SMTLs by southern blot. Body and muscle composition were estimated by bioimpedance and computed tomography, respectively. Physical performance was measured by jumping height and grip strength. HRT users and non-users did not differ in LTL or mean or minimum SMTL. Within-pair correlations were high in LTL (r = 0.69, p = .020) and in mean (r = 0.74, p = .014) and minimum SMTL (r = 0.88, p = .001). Body composition and performance were better in users than non-users. In analyses of individuals, LTL was associated with BMI (r 2 = 0.30, p = .030), percentage total body (r 2 = 0.43, p = .014), and thigh (r 2 = 0.55, p = .004) fat, while minimum SMTL was associated with fat-free mass (r 2 = 0.27, p = .020) and thigh muscle area (r 2 = 0.42, p = .016). We found no associations between HRT use and telomere length. Longer LTLs were associated with lower total and regional fat, while longer minimum SMTLs were associated with higher fat-free mass and greater thigh muscle area. This suggests that telomeres measured from different tissues may have different associations with measures of body composition.

With this study we investigated the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in human skeletal muscle regeneration. Young men ingested NSAID [1200 mg/d ibuprofen (IBU)] or placebo (PLA) daily for 2 wk before and 4 wk after an electrical stimulation-induced injury to the leg extensor muscles of one leg. Muscle biopsies were collected from the vastus lateralis muscles before and after stimulation (2.5 h and 2, 7, and 30 d) and were assessed for satellite cells and regeneration by immunohistochemistry and real-time RT-PCR, and we also measured telomere length. After injury, and compared with PLA, IBU was found to augment the proportion of ActiveNotch1(+) satellite cells at 2 d [IBU, 29 ± 3% vs. PLA, 19 ± 2% (means ± sem)], satellite cell content at 7 d [IBU, 0.16 ± 0.01 vs. PLA, 0.12 ± 0.01 (Pax7(+) cells/fiber)], and to expedite muscle repair at 30 d. The PLA group displayed a greater proportion of embryonic myosin(+) fibers and a residual ∼2-fold increase in mRNA levels of matrix proteins (all P < 0.05). Endomysial collagen was also elevated with PLA at 30 d. Minimum telomere length shortening was not observed. In conclusion, ingestion of NSAID has a potentiating effect on Notch activation of satellite cells and muscle remodeling during large-scale regeneration of injured human skeletal muscle.-Mackey, A. L., Rasmussen, L. K., Kadi, F., Schjerling, P., Helmark, I. C., Ponsot, E., Aagaard, P., Durigan, J. L. Q., Kjaer, M. Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication.

Background: Previous randomized controlled trials investigating exercise training programs in facioscapulohumeral muscular dystrophy (FSHD) patients are scarce and of short duration only. This study assessed the safety and efficacy of a 6-month home-ased exercise training program on fitness, muscle, and motor function in FSHD patients.

Methods: Sixteen FSHD patients were randomly assigned to training (TG) and control (CG) groups (both n=8) in a home-based exercise intervention. Training consisted of cycling 3 times weekly for 35minutes (combination of strength, high-intensity interval, and low-intensity aerobic) at home for 24 weeks. Patients in CG also performed an identical training program (CTG) after 24 weeks. The primary outcome was change in peak oxygen uptake (VO2 peak) measured every 6 weeks. The principal secondary outcomes were maximal quadriceps strength (MVC) and local quadriceps endurance every 12 weeks. Other outcome measures included maximal aerobic power (MAP) and experienced fatigue every 6 weeks, 6-minute walking distance every 12 weeks, and muscle characteristics from vastus lateralis biopsies taken pre- and postintervention.

Results: The compliance rate was 91% in TG. Significant improvements with training were observed in the VO2 peak (+19%, P= 0.002) and MAP by week 6 and further to week 24. Muscle endurance, MVC, and 6-minute walking distance increased and experienced fatigue decreased. Muscle fiber cross-sectional area and citrate synthase activity increased by 34% (P=0.008) and 46% (P=0.003), respectively. Dystrophic pathophysiologic patterns were not exacerbated. Similar improvements were experienced by TG and CTG.

Conclusions: A combined strength and interval cycling exercise-training program compatible with patients' daily professional and social activities leads to significant functional benefits without compromising muscle tissue.

The delivery of efficient nonpharmacological treatment to prevent the loss of muscle mass in older adults is a major challenge, and information on the combined effects of training and diet is particularly important. Here we aimed to evaluate the effects of 24 wk of resistance training combined with a healthy dietary approach (n-6/n-3 ratio < 2) in a population of healthy and physically active older women (65-70 years). The three-armed randomized controlled trial included a resistance training + healthy diet group (RT-HD), a resistance training group (RT), and controls (CON). All subjects included in the study were physically active and had low levels of serum inflammatory markers. In accordance with the dietary goals, the n-6/n-3 ratio dietary intake significantly decreased only in RT-HD by 42%. An increase in 1 repetition maximum in leg extension occurred in RT (+20.4%) and RT-HD (+20.8%), but not in CON. Interestingly, leg lean mass significantly increased only in RT-HD (+1.8%). While there were no changes in serum C-reactive protein and IL-6 levels, a significant decrease in serum level of the pro-inflammatory precursor arachidonic acid (-5.3 +/- 9.4%) together with an increase in serum n-3 docosahexaenoic acid (+8.3%) occurred only in RT-HD. Altogether, this study demonstrates that the effects of resistance training on muscle mass in healthy older adults can be optimized by the adoption of a healthy diet.

The impact of a 24-h ultraendurance exercise bout on systemic and local muscle inflammatory reactions was investigated in nine experienced athletes. Blood and muscle biopsies were collected before (Pre), immediately after the exercise bout (Post), and after 28 h of recovery (Post28). Circulating blood levels of leukocytes, creatine kinase (CK), C-reactive protein (CRP), and selected inflammatory cytokines were assessed together with the evaluation of the occurrence of inflammatory cells (CD3(+), CD8(+), CD68(+)) and the expression of major histocompatibility complex class I (MHC class I) in skeletal muscle. An extensive inflammatory cell infiltration occurred in all athletes, and the number of CD3(+), CD8(+), and CD68(+) cells were two- to threefold higher at Post28 compared with Pre (P < 0.05). The inflammatory cell infiltration was associated with a significant increase in the expression of MHC class I in muscle fibers. There was a significant increase in blood leukocyte count, IL-6, IL-8, CRP, and CK at Post. At Post28, total leukocytes, IL-6, and CK had declined, whereas IL-8 and CRP continued to increase. Increases in IL-1β and TNF-α were not significant. There were no significant associations between the magnitude of the systemic and local muscle inflammatory reactions. Signs of muscle degenerative and regenerative events were observed in all athletes with various degrees of severity and were not affected by the 24-h ultraendurance exercise bout. In conclusion, a low-intensity but very prolonged single-endurance exercise bout can generate a strong inflammatory cell infiltration in skeletal muscle of well-trained experienced ultraendurance athletes, and the amplitude of the local reaction is not proportional to the systemic inflammatory response.

Aims: Muscle satellite cells (SCs) are responsible for the regenerative events following muscle fibre injury. This study aimed to improve our understanding of SC behaviour in two models of muscle disorder with different pathological mechanisms and onset of disease.

Methods and results: Pax7(+)SC content was assessed in types I and II fibres of patients with Duchenne muscular dystrophy (DMD; n=9; age 132years), polymyositis/dermatomyositis (PM/DM; n=9; age 52 +/- 12years) and in controls (n=5; age 26 +/- 5years). Pax7(+)SCs number in type I and II fibres was higher (P<0.05) in DMD and in PM/DM compared to controls. Type I fibres were associated with a higher number of Pax7(+)SCs compared to type II fibres only in DMD; Pax7(+)SCs number in type I fibres was about threefold higher in DMD compared to PM/DM (P<0.05). In DMD, Pax7(+)SC content in small regenerating fibres (0.09 +/- 0.09 SCs/fibre) was similar to that in fibres from healthy skeletal muscle. The proportion of activated SCs (Ki-67(+)SCs) was fivefold lower in DMD (0.4 +/- 0.4%) compared to PM/DM (2.8 +/- 2%). Pax7(+) cells located outside the basal lamina were observed in DMD muscles only.

Conclusion: The capacity to generate new SCs is increased even in severely impaired muscles and a fibre type-specific enhancement of SC occurs in type I muscle fibres in DMD.

New insights suggest the existence of telomere regulatory mechanisms in several adult tissues. In this study, we aimed to assess in vivo telomere length and the presence of specific proteins involved in telomere regulation in a model of human skeletal muscle with (patients with dermatomyosis or polymyositis) and without ongoing regenerative events (healthy subjects). Mean (meanTRF) and minimal telomere (miniTRF) lengths and the expression of telomerase, tankyrase 1, TRF2 (telomeric repeat binding factor 2) and POT1 (protection of telomeres 1) were investigated in skeletal muscle samples from 12 patients (MYO) and 13 healthy subjects (CON). There was no significant shortening of telomeres in skeletal muscle from patients compared with control subjects (MYO, meanTRF length 11.0 ± 1.8 kbp and miniTRF length 4.7 ± 0.8 kbp; CON, meanTRF length 10.4 ± 1.1 kbp and miniTRF length 4.6 ± 0.5 kbp). Theoretically, telomere length can be controlled by endogenous mechanisms. Here, we show for the first time that expression levels of telomerase, tankyrase 1, TRF2 and POT1 were, respectively, six-, seven-, three- and fivefold higher in the nuclear fraction of skeletal muscle of MYO compared with CON (P < 0.05). This suggests the existence of endogenous mechanisms allowing for telomere regulation in skeletal muscle with ongoing cycles of degeneration and regeneration and a model where regulatory factors are possibly involved in the protection of skeletal muscle telomeres.