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Our understanding of skeletal muscle structural and functional alterations during unloading has increased in recent decades, yet the molecular mechanisms underpinning these changes have only started to be unraveled. The purpose of the current investigation was to assess changes in skeletal muscle gene expression after 21 days of bed rest, with a particular focus on predicting upstream regulators of muscle disuse. Additionally, the association between differential microRNA expression and the transcriptome signature of bed rest were investigated. mRNAs from m. vastus lateralis biopsies obtained from 12 men before and after the bed rest were analyzed using a microarray. There were 54 significantly up-regulated probesets after bed rest, whereas 103 probesets were down-regulated (FDR 10%; fold-change cut-off ≥1.5). Amongst the up-regulated genes, transcripts related to denervation-induced alterations in skeletal muscle were identified, e.g. CHRND and perinatal myosin. The most down-regulated transcripts were functionally enriched for mitochondrial genes and genes involved in mitochondrial biogenesis, followed by a large number of contractile fiber components. Upstream regulator-analysis identified a robust inhibition of the MEF2 family, in particular MEF2C, which was suggested to act upstream of several key down-regulated genes, most notably PGC-1α/PPARs and CRSP3. Only a few microRNAs were identified as playing a role in the overall transcriptome picture induced by sustained bed rest. Our results suggest that the MEF2 family is a key regulator underlying the transcriptional signature of bed rest, and hence ultimately also skeletal muscle alterations induced by systemic unloading in humans., QC 20180824

As aerobic exercise (AE) may interfere with adaptations to resistance exercise (RE), this study explored acute and chronic responses to consecutive AE (similar to 45 min cycling) and RE (4 X 7 maximal knee extensions) vs. RE only. Ten men performed acute unilateral AE + RE interspersed by 15 min recovery. The contralateral leg was subjected to RE. This exercise paradigm was then implemented in a 5-wk training program. Protein phosphorylation, gene expression, and glycogen content were assessed in biopsies obtained from the vastus lateralis muscle of both legs immediately before and 3 h after acute RE. Quadriceps muscle size and in vivo torque were measured, and muscle samples were analyzed for citrate synthase activity and glycogen concentration, before and after training. Acute AE reduced glycogen content (32%; P < 0.05) and increased (P < 0.05) phosphorylation of AMPK (1.5-fold) and rpS6 (1.3-fold). Phosphorylation of p70S6K and 4E-BP1 remained unchanged. Myostatin gene expression was downregulated after acute AE + RE but not RE. Muscle size showed greater (P < 0.05) increase after AE + RE (6%) than RE (3%) training. Citrate synthase activity (18%) and endurance performance (22%) increased (P < 0.05) after AE + RE but not RE. While training increased (P < 0.05) in vivo muscle strength in both legs, normalized and concentric torque increased after RE only. Thus AE activates AMPK, reduces glycogen stores, and impairs the progression of concentric force, yet muscle hypertrophic responses to chronic RE training appear not to be compromised.

Background: Resistance exercise comprising eccentric (ECC) muscle actions enhances muscle strength and function to aid stroke patients in conducting daily tasks. The purpose of this study was to assess the efficacy of a novel ECC-overload flywheel resistance exercise paradigm to induce muscle and functional performance adaptations in chronic stroke patients. Methods: Twelve patients (similar to 8 years after stroke onset) performed 4 sets of 7 coupled concentric (CON) and ECC actions using the affected limb on a flywheel leg press (LP) device twice weekly for 8 weeks. Maximal CON and ECC isokinetic torque at 30, 60 and 90 degrees/s, isometric knee extension and LP force, and CON and ECC peak power in LP were measured before and after training. Balance (Berg Balance Scale, BBS), gait (6-Min Walk test, 6MWT; Timed-Up-and-Go, TUG), functional performance (30-s Chair-Stand Test, 30CST), spasticity (Modified Ashworth Scale) and perceived participation (Stroke Impact Scale, SIS) were also determined. Results: CON and ECC peak power increased in both the trained affected (34 and 44%; P < 0.01), and the untrained, non-affected leg (25 and 34%; P < 0.02). Power gains were greater (P = 0.008) for ECC than CON actions. ECC isokinetic torque at 60 and 90 degrees/s increased in the affected leg (P < 0.04). The increase in isometric LP force for the trained, affected leg across tests ranged 10-20% (P < 0.05). BBS (P = 0.004), TUG (P = 0.018), 30CST (P = 0.024) and SIS (P = 0.058) scores improved after training. 6MWT and spasticity remained unchanged. Conclusions: This novel, short-term ECC-overload flywheel RE training regime emerges as a valid, safe and viable method to improve muscle function, balance, gait and functional performance in men and women suffering from chronic stroke.

Introduction: A truncated PGC-1 alpha splice variant (PGC-1 alpha 4) has been implicated in the regulation of resistance exercise (RE)-induced muscle hypertrophy, and basal expression levels said to be augmented in response to concurrent aerobic (AE) and RE training.Aim: The current study investigated human muscle truncated and non-truncated PGC-1a transcripts in response to both acute and chronic RE, and with or without preceding AE (AE+RE).Methods: Ten men performed 5 weeks of unilateral AE+RE and RE training.Before (untrained) and after (trained) this intervention, PGC-1a transcripts were assessed in vastus lateralis muscle biopsies obtained before and 3 h after acute RE, with or without preceding AE.Additionally, samples were collected 72 h after the last exercise bout of the training programme.Results: The truncated splice variant increased (P < 0.05) its expression after acute exercise regardless of mode. However, the expression was greater (P < 0.05) after AE+RE than RE. Other PGC-1a transcripts showed similar response. Truncated transcripts originated from both the alternative and proximal promoter, and AE+RE increasedPGC-1 alpha expression from both promoter sites. RE induced transcripts from the alternative promoter only. PGC-1 alpha expressions after acute exercise were comparable across isoforms in both untrained and trained muscle. Steady-state levels of isoforms were unchanged after 5-week training (P > 0.05). Exercise-induced expression of PGC-1a variants did not correlate with changes in muscle size or strength (P > 0.05).Conclusion: Our results do not support the view that truncated PGC-1a coordinates exercise-induced hypertrophy in human skeletal muscle.Rather, all PGC-1 alpha isoforms appear to be regulated transiently in response to acute exercise and regardless of mode.

This study tested the hypothesis that chronic aerobic and resistance exercise (AE+RE) would elicit greater muscle hypertrophy than resistance exercise only (RE). Ten men (25±4 yrs) performed 5 wks unilateral knee extensor AE+RE. The opposing limb was subjected to RE. AE completed 6 hrs prior to RE, consisted of ~45 min one-legged cycle ergometry. RE comprised 4 x 7 maximal concentric-eccentric knee extensions. Various indices of in vivo knee extensor function were measured before and after training. Magnetic resonance imaging (MRI) assessed m. quadricep femoris (QF) cross-sectional area (CSA), volume, and signal intensity (SI). Biopsies obtained from m. vastus lateralis determined fiber CSA, enzyme levels and gene expression of myostatin, atrogin-1, MuRF-1, PGC-1α and VEGF. Increases (P < 0.05) in isometric strength and peak power, respectively were comparable in AE+RE (9 and 29%) and RE (11 and 24%). AE+RE showed greater increase (14%; P < 0.05) in QF volume than RE (8%). Muscle fiber CSA increased 17% after AE+RE (P < 0.05) and 9% after RE (P > 0.05). QF SI increased (12%; P < 0.05) after AE+RE, but not RE. Neither AE+RE nor RE showed altered mRNA-levels. Citrate Synthase activity increased (P < 0.05) after AE+RE. The results suggest that the increased aerobic capacity shown with AE+RE, was accompanied by a more robust increase in muscle size compared with RE. While this response was not carried over to greater improvement in muscle function, it remains that intense AE can be executed prior to RE without compromising performance outcome.