Validation of a New Semi-Automated Technique to Evaluate Muscle Capillarization.

The method of capillary domains has often been used to study capillarization of skeletal and heart muscle. However, the conventional data processing method using a digitizing tablet is an arduous and time-consuming task. Here we compare a new semi-automated capillary domain data collection and analysis in muscle tissue with the standard capillary domain method. The capillary density (1481 ± 59 vs. 1447 ± 54 caps mm(-2); R(2):0.99; P < 0.01) and heterogeneity of capillary spacing (0.085 ± 0.002 vs. 0.085 ± 0.002; R(2):0.95; P < 0.01) were similar in both methods. The fiber cross-sectional area correlated well between the methods (R(2):0.84; P < 0.01) and did not differ significantly (~8 % larger in the old than new method at P = 0.08). The latter was likely due to differences in outlining the contours between the two methods. In conclusion, the semi-automated method gives quantitatively and qualitatively similar data as the conventional method and saves a considerable amount of time

Blunted angiogenesis and hypertrophy are associated with increased fatigue resistance and unchanged aerobic capacity in old overloaded mouse muscle.

We hypothesize that the attenuated hypertrophic response in old mouse muscle is (1) partly due to a reduced capillarization and angiogenesis, which is (2) accompanied by a reduced oxidative capacity and fatigue resistance in old control and overloaded muscles, that (3) can be rescued by the antioxidant resveratrol. To investigate this, the hypertrophic response, capillarization, oxidative capacity, and fatigue resistance of m. plantaris were compared in 9- and 25-month-old non-treated and 25-month-old resveratrol-treated mice. Overload increased the local capillary-to-fiber ratio less in old (15 %) than in adult (59 %) muscle (P < 0.05). Although muscles of old mice had a higher succinate dehydrogenase (SDH) activity (P < 0.05) and a slower fiber type profile (P < 0.05), the isometric fatigue resistance was similar in 9- and 25-month-old mice. In both age groups, the fatigue resistance was increased to the same extent after overload (P < 0.01), without a significant change in SDH activity, but an increased capillary density (P < 0.05). Attenuated angiogenesis during overload may contribute to the attenuated hypertrophic response in old age. Neither was rescued by resveratrol supplementation. Changes in fatigue resistance with overload and aging were dissociated from changes in SDH activity, but paralleled those in capillarization. This suggests that capillarization plays a more important role in fatigue resistance than oxidative capacity

Effects of resistance training, detraining, and retraining on strength and functional capacity in elderly

Background: The interruption of training (detraining) results in loss of the gains acquired. Partial retention could occur after detraining, and variation in training stimuli may optimize retraining adaptations. Aim: To evaluate the effect of a resistance-retraining program on strength and functional capacity performance after a detraining period. Methods: Ten elderly men and women (63–68 years) completed 12 weeks of training, 16 weeks of detraining, and 8 weeks of retraining. One-repetition maximum (1-RM) at 45° leg press, maximum isometric knee extension torque, rate of torque development (RTD), 30-s sit-to-stand, timed up and go, and stair ascent and descent tests were assessed. Results: The 1-RM increased after training (p 0.05). For RTD and 30-s sit-to-stand, there was an increase after retraining when compared to pre-training values (p < 0.05). For timed up and go and stair ascent and descent, reductions were observed between pre-training and post-training periods (p < 0.05), only timed up and go increased after the detraining period (p < 0.01). Discussion: After 16 weeks of detraining, the maximum strength did not return to baseline levels, and a retraining with explosive strength exercise sessions can recover maximum strength gains, RTD, and functional capacity at the same level obtained after a detraining period. Conclusions: The inclusion of an explosive strength session in retraining period improves RTD and 30-s sit-to-stand performance and can accelerate the recovery of strength after a detraining period.</p

Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity

The role of IGF-1 signaling in skeletal muscle atrophy

Insulin-like growth factor 1 (IGF-1) is a key anabolic growth factor stimulating phosphatidylinositol 3-kinase (PI3K)/Akt signaling which is well known for regulating muscle hypertrophy. However, the role of IGF-1 in muscle atrophy is less clear. This review provides an overview of the mechanisms via which IGF-1 signaling is implicated in several conditions of muscle atrophy and via which mechanisms protein turnover is altered. IGF-1/PI3K/Akt signaling stimulates the rate of protein synthesis via p70S6Kinase and p90 ribosomal S6 kinase and negatively regulates protein degradation, predominantly by its inhibiting effect on proteasomal and lysosomal protein degradation. Caspase-dependent protein degradation is also attenuated by IGF/PI3K/Akt signaling, whereas evidence for an effect on calpain-dependent protein degradation is inconclusive. IGF-1/PI3K/Akt signaling reduces during denervation-, unloading-, and joint immobilization-induced muscle atrophy, whereas IGF-1/PI3K/Akt signaling seems unaltered during aging-associated muscle atrophy. During denervation and aging, IGF-1 overexpression or injection counteracts denervation- and aging-associated muscle atrophy, despite enhanced anabolic resistance with regard to IGF-1 signaling with aging. It remains unclear whether pharmacological stimulation of IGF-1/PI3K/Akt signaling attenuates immobilization- or unloading-induced muscle atrophy. Exploration of the possibilities to interfere with IGF-1/PI3K/Akt signaling reveals that microRNAs targeting IGF-1 signaling components are promising targets to counterbalance muscle atrophy. Overall, the findings summarized in this review show that in disuse conditions, but not with aging, IGF-1/PI3K/Akt signaling is attenuated and that in some conditions stimulation of this pathway may alleviate skeletal muscle atrophy

Past, present, and future perspective of targeting myostatin and related signaling pathways to counteract muscle atrophy

Myostatin was identified more than 20 years ago as a negative regulator of muscle mass in mice and cattle. Since then, a wealth of studies have uncovered the potential involvement of myostatin in muscle atrophy and sparked interest in myostatin as a promising therapeutic target to counteract decline of muscle mass in patients afflicted with different muscle-wasting conditions. Insight in the molecular mechanism of myostatin signaling and regulation of myostatin activity has resulted in the identification of specific treatments to inhibit myostatin signaling and related signaling pathways. Currently, several treatments that target myostatin and related proteins have been evaluated in preclinical animal models of muscle wasting, and some potential therapies have progressed to clinical trials. However, studies also revealed potential downsides of myostatin targeting in skeletal muscle and other tissues, which raises the question if myostatin is indeed a valuable target to counteract muscle atrophy. In this review we provide an updated overview of the molecular mechanisms of myostatin signaling, the preclinical evidence supporting a role for myostatin and related proteins in muscle atrophy, and the potential issues that arise when targeting myostatin. In addition, we evaluate the current clinical status of different treatments aimed at inhibiting myostatin and discuss future perspectives of targeting myostatin to counteract muscle atrophy