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Background While muscle regeneration has been extensively studied in animal and cell culture models, in vivo myogenesis in adult human skeletal muscle has not been investigated in detail. Methods Using forced lengthening contractions induced by electrical stimulation, we induced myofibre injury in young healthy males. Muscle biopsies were collected from the injured leg 7 and 30 days after muscle injury and from the uninjured leg as a control. Immuno-stained single muscle fibres and muscle cross sections were studied by wide-field and confocal microscopy. Samples were also studied at the ultra-structural level by electron microscopy. Results Microscopy of single muscle fibres in 3 dimensions revealed a repeating pattern of necrotic and regenerating zones along the length of the same myofibre, characterised by extensive macrophage infiltration alongside differentiating myogenic progenitor cells and myotubes: the hallmarks of myogenesis. The myofibre basement membrane was preserved during these processes and interestingly was seen at a later stage as a second basement membrane surrounding the regenerating fibres. Conclusions This is the first work to document in vivo myogenesis in humans in detail and highlights the importance of the basement membrane in the process of regeneration. In addition, it provides insight into parallels between the regeneration of adult skeletal muscle in mouse and man, confirming that this model may be a useful tool in investigating myofibre and matrix formation, as well as specific cell types, during regeneration from the perspective of human muscle.

The extent of inter-individual variability in response to heavy resistance exercise training (HReT), and the possible existence of non-responders, remains unclear. This study aimed to determine the degree of variability in response to prolonged HReT in healthy older men. We conducted a secondary analysis of an 8- and 16-week intervention involving thrice-weekly HReT (EX) or continuation of a sedentary lifestyle (SED). Fifty-eight healthy men (age 72 ± 5) were randomized to EX (n = 38) or SED (n = 20). Assessments were conducted at baseline, 8-weeks, and 16-weeks for five outcomes: maximal voluntary contraction strength (MVC), rate of force development (RFD), quadriceps cross-sectional area (qCSA), and type I and II myofibre cross-sectional area (fCSA). Inter-individual variability was assessed using the standard deviation of individual responses (SDIR). Individual changes relative to a Typical Error were used to classify responders as Poor, Trivial, Robust, or Excellent. 16 weeks of EX led to group-level increases in MVC (19 ± 14%), RFD (58 ± 80%), qCSA (3 ± 4%), and type II fCSA (14 ± 25%), with no changes in SED. Substantial inter-individual variability was observed. After 16 weeks, 82% of EX participants were classified as Robust or Excellent responders; only 5% were Poor responders. Training compliance and 1RM progression did not explain this variability. Lower baseline levels were linked to greater improvements but did not fully account for response differences. This study provides strong evidence of inter-individual variability in response to HReT among healthy older men. Given the rarity of true non-responders, our data support HReT as the universally recommended first-line strategy for enhancing muscle mass and strength.

Background Age‐related loss of strength is disproportionally greater than the loss of mass, suggesting maladaptations in the neuro‐myo‐tendinous system. Myofibers are often misshaped in aged and diseased muscle, but systematic analyses of large sample sets are lacking. Our aim was to investigate myofiber shape in relation to age, exercise, myofiber type, species and sex. Methods Vastus lateralis muscle biopsies (n = 265) from 197 males and females, covering an age span of 20–97 years, were examined. The gastrocnemius and soleus muscles of 11 + 22‐month‐old male C57BL/6 mice were also examined. Immunofluorescence and ATPase stainings of muscle cross‐sections were used to measure myofiber cross‐sectional area (CSA) and perimeter. From these, a shape factor index (SFI) was calculated in a fibre‐type‐specific manner (type I/II in humans; type I/IIa/IIx/IIb in mice), with higher values indicating increased deformity. Heavy resistance training (RT) was performed three times per week for 3–4 months by a subgroup (n = 59). Correlation analyses were performed comparing SFI and CSA with age, muscle mass, maximal voluntary contraction (MVC), rate of force development and specific force (MVC/muscle mass). Results In human muscle, SFI was positively correlated with age for both type I (R2 = 0.20) and II (R2 = 0.38) myofibers. When subjects were separated into age cohorts, SFI was lower for type I (4%, P < 0.001) and II (6%, P < 0.001) myofibers in young (20–36) compared with old (60–80) and higher for type I (5%, P < 0.05) and II (14%, P < 0.001) myofibers in the oldest old (>80) compared with old. The increased SFI in old muscle was observed in myofibers of all sizes. Within all three age cohorts, type II myofiber SFI was higher than that for type I myofiber (4–13%, P < 0.001), which was also the case in mice muscles (8–9%, P < 0.001). Across age cohorts, there was no difference between males and females in SFI for either type I (P = 0.496/0.734) or II (P = 0.176/0.585) myofibers. Multiple linear regression revealed that SFI, after adjusting for age and myofiber CSA, has independent explanatory power for 8/10 indices of muscle mass and function. RT reduced SFI of type II myofibers in both young and old (3–4%, P < 0.001). Conclusions Here, we identify type I and II myofiber shape in humans as a hallmark of muscle ageing that independently predicts volumetric and functional assessments of muscle health. RT reverts the shape of type II myofibers, suggesting that a lack of myofiber recruitment might lead to myofiber deformity.

Ageing leads to a decline in white matter microstructure and dexterous function of the hand. In adolescents, it has previously been shown that the degree of right-left asymmetry in the corticospinal tract (CST) is linearly related with right-left asymmetry in dexterity. Here, we tested whether this association is also expressed in older adults. Participants completed a simple circle drawing task with their right and left hand as a measure of dexterity and underwent whole-brain diffusion weighted imaging at 3 Tesla (n = 199; aged 60–72 years). Fractional anisotropy and mean diffusivity of right and left CST were extracted from a manually defined region-of-interest. Linear regression analyses were computed to replicate the analyses in adolescents. Frequentist analyses were complemented with a Bayesian analytical framework. Outcome measures were compared with those previously reported in adolescents (aged 11–16 years). Asymmetries in white matter microstructure of the CST were evident and comparable to the degree of lateralisation observed in adolescence. Similarly, asymmetries in dexterity were evident, but to a lesser degree than in adolescents. Unlike in adolescents, we found no evidence of a linear relationship between asymmetries in CST microstructure and dexterity. Complementary Bayesian regression analysis provided moderate evidence in favour of the null hypothesis, pointing towards a lack of association between the structural and functional measures of right-left asymmetry. Our findings are compatible with the notion that, by late adulthood, a diverging impact of age on white matter structure and dexterous hand function dilutes the structure-function relationship between CST microstructure and manual proficiency that has been reported in adolescents.

Background Resistance training and other forms of physical exercise are commonly suggested to promote brain health, yet the relationship between resistance training and brain structure in aging is poorly understood. We examined the short- and long-term influence of one year of supervised resistance training at two different loadings on brain structure in aging. Methods In the LISA (LIve active Successful Ageing) study, well-functioning older adults at retirement age (mean age: 66 ± 2 years) were randomized to one year of heavy resistance training (HRT), moderate intensity training (MIT), or a non-exercising control group (CON). Magnetic resonance imaging (MRI) of the brain was performed at baseline, 1-, 2-, and 4-years follow ups. Trajectories of total grey matter, hippocampus, dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and white matter hyperintensities were analyzed in relation to changes in muscle strength. Results Individuals ( n  = 276) with MRI scans at all 4 timepoints were included (HRT, n  = 96; MIT, n  = 95; CON, n  = 85). Total grey matter volume decreased with time across all groups (F 3,819  = 231.549, p  < 0.001, η 2 = 0.46), as did hippocampal (F 3,819  = 310.07, p  < 0.001, η 2 = 0.53), vlPFC (F 3,818  = 74.380, p  < 0.001, η 2 = 0.21), and dlPFC (F 3,818  = 3.640, p = 0.013, η 2 = 0.01) volumes. White matter hyperintensity volumes increased (F 3,819  = 101.876, p  < 0.001, η 2 = 0.27). There were no significant group x time interactions for any of the brain structures. Additional cortical and subcortical vertex-wise analyses showed no group differences. Change in isometric leg strength was weakly associated with change in white matter hyperintensity volume across all individuals (r 2  = 0.01, p  = 0.048). Conclusions One year of resistance training in well-functioning older adults at retirement age did not influence volume changes in selected brain regions over a 4-year period. Trial registration The study was approved by the regional ethics committee and registered on clinicaltrials.gov 2014–04-24 (NCT02123641).

Prematurity has physical consequences, such as lower birth weight, decreased muscle mass and increased risk of adult‐onset metabolic disease. Insulin‐like growth factor 1 (IGF‐1) has therapeutic potential to improve the growth and quality of muscle and tendon in premature births, and thus attenuate some of these sequalae. We investigated the effect of IGF‐1 on extensor carpi radialis muscle and biceps brachii tendon of preterm piglets. The preterm group consisted of 19‐day‐old preterm (10 days early) piglets, treated with either IGF‐1 or vehicle. Term controls consisted of groups of 9‐day‐old piglets (D9) and 19‐day‐old piglets (D19). Muscle samples were analysed by immunofluorescence to determine the cross‐sectional area (CSA) of muscle fibres, fibre type composition, satellite cell content and central nuclei‐containing fibres in the muscle. Tendon samples were analysed for CSA, collagen content and maturation, and vascularization. Gene expression of the tendon was measured by RT‐qPCR. Across all endpoints, we found no significant effect of IGF‐1 treatment on preterm piglets. Preterm piglets had smaller muscle fibre CSA compared to D9 and D19 control group. Satellite cell content was similar across all groups. For tendon, we found an effect of age on tendon CSA, and mRNA levels of COL1A1, tenomodulin and scleraxis. Immunoreactivity for elastin and CD31, and several markers of tendon maturation, were increased in D9 compared to the preterm piglets. Collagen content was similar across groups. IGF‐1 treatment of preterm‐born piglets does not influence the growth and maturation of skeletal muscle and tendon. What is the central question of this study? Does infusion of insulin‐like growth factor‐1 in preterm piglets stimulate growth parameters of muscle and tendon? What is the main finding and its importance? IGF‐1 treatment of preterm born piglets does not influence growth and maturation of skeletal muscle and tendon. This adds to the current knowledge on the effect of IGF‐1 on muscle and tendon growth, and is relevant for future research in potential therapies for premature infants.

Various studies have reported an association between physical activity and grey matter volumes. Some studies have suggested that this relationship may be moderated by sex, yet the direction is still under debate. Focusing on hippocampus and dorsolateral prefrontal cortex (dlPFC), we tested whether the association between regional grey matter volumes and self-reported physical activity differs between women and men. We examined this interaction in five European cohorts from the Lifebrain consortium (n = 1809; age range: 18–88 years). Effect sizes were first determined by linear models run separately for each cohort, then pooled across datasets in a random-effects meta-analysis. Contrary to our hypotheses, there was no evidence of a relationship between physical activity and hippocampal or dlPFC volumes, nor was there a moderation by sex. Our null findings raise the question of whether self-report questionnaires of physical activity, which commonly feature in big datasets, are sufficiently sensitive to capture a—presumably modest—association between physical activity levels and grey matter outcomes. We conclude that the reliance on self-report questionnaires of physical activity is sub-optimal for brain-behaviour analyses.

Background Regular loading of tendons may counteract the negative effects of aging. However, the influence of strength training loading magnitude on tendon mechanical properties and its relation to matrix collagen content and collagen cross-linking is sparsely described in older adults. The purpose of the present study was to compare the effects of moderate or high load resistance training on tendon matrix and its mechanical properties. Methods Seventeen women and 19 men, age 62–70 years, were recruited and randomly allocated to 12 months of heavy load resistance training (HRT), moderate load resistance training (MRT) or control (CON). Pre- and post-intervention testing comprised isometric quadriceps strength test (IsoMVC), ultrasound based testing of in vivo patellar tendon (PT) mechanical properties, MRI-based measurement of PT cross-sectional area (CSA), PT biopsies for assessment of fibril morphology, collagen content, enzymatic cross-links, and tendon fluorescence as a measure of advanced glycation end-products (AGEs). Results Thirty three participants completed the intervention and were included in the data analysis. IsoMVC increased more after HRT (+ 21%) than MRT (+ 8%) and CON (+ 7%) ( p  < 0.05). Tendon stiffness (p < 0.05) and Young’s modulus ( p  = 0.05) were also differently affected by training load with a reduction in CON and MRT but not in HRT. PT-CSA increased equally after both MRT and HRT. Collagen content, fibril morphology, enzymatic cross-links, and tendon fluorescence were unaffected by training. Conclusion Despite equal improvements in tendon size after moderate and heavy load resistance training, only heavy. load training seemed to maintain tendon mechanical properties in old age. The effect of load magnitude on tendon biomechanics was unrelated to changes of major load bearing matrix components in the tendon core. The study is a sub-study of the LISA study, which was registered at http://clinicaltrials.gov (NCT02123641) April 25th 2014.

Background Sarcopenia represents a major clinical and societal challenge facing rapidly aging populations. Accessible and specific biomarkers represent valuable tools, both in diagnosis and assessing the efficacy of therapeutic interventions. C‐terminal agrin fragment (CAF) is the most commonly used blood‐based biomarker of neuromuscular junction degradation in aging, inactivity and disease, but large unexplained interindividual variation exists, limiting its diagnostic and prognostic value. Exercise and medication may explain some of this variation. The aim of this study was to investigate the influence of a single bout (1EX) or 48 bouts (48EX) of heavy resistance exercise (EX), with or without angiotensin II type I receptor blocker (losartan (LOS)) supplementation, on serum CAF levels in healthy older men. Methods Eighty‐three healthy, normotensive older men were enrolled in one of two randomized placebo (PLA) controlled trials. 1EX: 25 participants (EX ± LOS), with a mean age of 70 ± 7 years, had blood drawn before and after (4.5 h, Days 1, 4 and 7) a single bout of unilateral heavy resistance exercise of the quadriceps muscles. 48EX: at baseline, and after 8 and 16 weeks of a progressive heavy resistance exercise program, 58 participants (LOS‐EX, n = 20; LOS‐SED, n = 20; PLA‐EX, n = 18), with a mean age of 72 ± 5 years, had blood drawn, and specific force (strength per unit mass) was measured by dynamometer and magnetic resonance imaging of the quadriceps muscles. Serum CAF was measured by ELISA. Results At baseline, CAF showed weak correlations with age and leg lean mass (both R2 = 0.07, p < 0.05). With 48EX, specific force increased in both EX groups (LOS‐EX + PLA‐EX) by 13%–14% at 8 weeks and 14%–17% at 16 weeks (p < 0.0001), with no change in LOS‐SED (p > 0.05), confirming the efficacy of the 48EX program. Serum CAF increased in LOS‐EX and LOS‐SED by 4%–7% at 8 weeks and 7%–9% at 16 weeks (p < 0.005) respectively, with no change in PLA‐EX (p > 0.05). 1EX reduced CAF by 8% 1 day postexercise (p < 0.05), with no correlation to circulating creatine kinase levels (p > 0.05), a marker of muscle damage. Conclusions Serum CAF was unaffected by 16 weeks of EX but increased by LOS supplementation. 1EX, performed with one leg, acutely lowered serum CAF, albeit with substantial interindividual variability. These findings collectively identify novel stimuli of serum CAF turnover—drug interaction and time from last exercise bout to blood sampling. These findings add value to CAF as a neuromuscular biomarker and highlight important experimental design aspects for future clinical studies.

Important insights concerning the molecular basis of skeletal muscle disuse-atrophy and aging related muscle loss have been obtained in cell culture and animal models, but these regulatory signaling pathways have not previously been studied in aging human muscle. In the present study, muscle atrophy was induced by immobilization in healthy old and young individuals to study the time-course and transcriptional factors underlying human skeletal muscle atrophy. The results reveal that irrespectively of age, mRNA expression levels of MuRF-1 and Atrogin-1 increased in the very initial phase (2-4 days) of human disuse-muscle atrophy along with a marked reduction in PGC-1α and PGC-1β (1-4 days) and a ~10% decrease in myofiber size (4 days). Further, an age-specific decrease in Akt and S6 phosphorylation was observed in young muscle within the first days (1-4 days) of immobilization. In contrast, Akt phosphorylation was unchanged in old muscle after 2 days and increased after 4 days of immobilization. Further, an age-specific down-regulation of MuRF-1 and Atrogin-1 expression levels was observed following 2 weeks of immobilization, along with a slowing atrophy response in aged skeletal muscle. Neither the immediate loss of muscle mass, nor the subsequent age-differentiated signaling responses could be explained by changes in inflammatory mediators, apoptosis markers or autophagy indicators. Collectively, these findings indicate that the time-course and regulation of human skeletal muscle atrophy is age dependent, leading to an attenuated loss in aging skeletal muscle when exposed to longer periods of immobility-induced disuse.