Palmitoylethanolamide Does Not Affect Recovery from Exercise-Induced Muscle Damage in Healthy Males.

INTRODUCTION: Strenuous eccentric exercise (EE) induces microstructural muscle damage, which decreases muscle performance. Palmitoylethanolamide (PEA) exerts analgesic and anti-inflammatory effects in clinical pain conditions and preclinical models of experimentally induced-inflammation. This might hold clues for improved recovery from EE. Therefore, the current study evaluates the effect of PEA supplementation on functional and molecular responses to a single EE bout. METHODS: Eleven healthy male participants were included in a double-blind crossover study in which they received PEA (350 mg Levagen+) or placebo (maltodextrin) supplements, in a randomized order. In each experimental condition participants performed an acute bout of EE (24x10 eccentric contractions of the knee extensors on an isokinetic dynamometer). At baseline, 24 (D1), 48 (D2), 72 (D3) and 120 h (D5) following EE, maximal voluntary contraction and jump height were measured. Blood samples were collected at baseline and on D1-D5, and muscle biopsies were collected at baseline and on D2. Perceived muscle soreness, sleep quality and food intake were recorded daily. RESULTS: Muscle strength and jump height decreased following EE (up to ~40 and ~ 17% respectively; Ptime < 0.05) in both conditions. This drop was accompanied by an increase in plasma creatine kinase and perceived muscle soreness (Ptime < 0.05). Furthermore, EE, but not PEA, increased the expression of the myogenic marker Pax7 and of the catabolic markers p-FoxO1-3a, p62 and LC3BII/I (Ptime < 0.05). CONCLUSIONS: PEA supplementation does not improve muscle soreness, muscle strength and jump performance following a single EE bout. Additionally, PEA supplementation had no effect on local or systemic markers of muscle damage, catabolism or regeneration.

The molecular signature of the peripheral cannabinoid receptor 1 antagonist AM6545 in adipose, liver and muscle tissue.

The endocannabinoid system plays an important role in the regulation of metabolism, growth and regeneration of peripheral tissues, including liver, adipose and muscle tissue. Studies in cells, rodents and humans showed that cannabinoid receptor 1 (CB1) antagonist treatment is an effective strategy to improve features of metabolic health such as substrate metabolism, at least in models of metabolic dysregulation. However, acute signaling events that might induce these metabolic adaptations are not understood. It is not clear whether, and to which extent, a single treatment with a CB1 antagonist induces acute effects in peripheral, metabolic tissues. Therefore, the present study compared the phosphorylation status of signaling pathways and metabolic markers in liver, adipose and muscle tissue of mice treated with the peripherally restricted CB1 antagonist AM6545 and vehicle-treated mice. Protein kinase A phosphorylation was downregulated in white and brown adipose tissue, whereas the mitogen-activated protein kinase, phospho-extracellular signal-regulated kinase, was higher in liver, white adipose and muscle tissue of AM6545-treated mice. Additionally, Akt-mammalian target of rapamycin activation was higher in all tissues of AM6545-treated mice, whereas the phosphorylation status of metabolic markers remained unaffected. These data indicate that acute CB1 antagonism is effective to induce phosphorylation events of signaling cascades and metabolic markers in metabolic tissues of healthy, lean mice within a 90-min time window. The observed adaptations to AM6545 treatment do not fully align with earlier in vitro and in vivo findings, which could be ascribed to differences in cell type, exposure intensity (dose and time), health status and species.

Endocannabinoid remodeling in murine cachexic muscle associates with catabolic and metabolic regulation.

Muscle degeneration is a common feature in cancer cachexia that cannot be reversed. Recent advances show that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1), regulates muscle processes, including metabolism, anabolism and regenerative capacity. However, it is unclear whether muscle endocannabinoids, their receptors and enzymes are responsive to cachexia and exercise. Therefore, this study investigated whether cachexia and exercise affected muscle endocannabinoid signaling, and whether CB1 expression correlated with markers of muscle anabolism, catabolism and metabolism. Male BALB/c mice were injected with PBS (CON) or C26 colon carcinoma cells (C26) and had access to wheel running (VWR) or remained sedentary (n = 5-6/group). Mice were sacrificed 18 days upon PBS/tumor cell injection. Cachexic mice exhibited a lower muscle CB1 expression (-43 %; p < 0.001) and lower levels of the endocannabinoid anandamide (AEA; -22 %; p = 0.044), as well as a lower expression of the AEA-synthesizing enzyme NAPE-PLD (-37 %; p < 0.001), whereas the expression of the AEA degrading enzyme FAAH was higher (+160 %; p < 0.001). The 2-AG-degrading enzyme MAGL, was lower in cachexic muscle (-34 %; p = 0.007), but 2-AG and its synthetizing enzyme DAGLß were not different between CON and C26. VWR increased muscle CB1 (+25 %; p = 0.005) and increased MAGL expression (+30 %; p = 0.035). CB1 expression correlated with muscle mass, markers of metabolism (e.g. p-AMPK, PGC1α) and of catabolism (e.g. p-FOXO, LC3b, Atg5). Our findings depict an emerging role of the endocannabinoid system in muscle physiology. Future studies should elaborate how this translates into potential therapies to combat cancer cachexia, and other degenerative conditions.

Sensor- and equation-based sit-to-stand power: The effect of age and functional limitations.

Estimating lower-limb muscle power during sit-to-stand (STS) tests is feasible for large-scale implementation. This study investigated 1) whether age, functional limitations and sex have an influence on the movement strategy and power production during STS; and 2) potential differences between STS power estimated with either a simple equation or a sensor. Five-repetition STS data of 649 subjects (♂352 ♀297) aged 19 to 93 years were included. Subjects were divided in different age groups and levels of functioning. A body-fixed sensor measured (sub)durations, trunk movement (flexion/extension) and STS muscle power (Psensor). Additionally, mean STS muscle power was calculated by a mathematic equation (Alcazar et al., 2018b)Results revealed that 1) older subjects and women showed greater trunk flexion before standing up than younger subjects and men, respectively (both p < 0.001); 2) well-functioning adults seemed to have the tendency to not extend the trunk fully during the sit-to-stand transition (mean difference extension - flexion range = -15.3° to -13.1°, p < 0.001); 3) mobility-limited older adults spent more time in the static sitting and standing positions than their well-functioning counterparts (all p < 0.001); 4) STS power decreased with age and was lower in women and in limited-functioning subjects compared to men and well-functioning subjects, respectively (p < 0.05); 5) Pformula was highly related to Psensor (ICC = 0.902, p < 0.001); and 6) Pformula demonstrated higher values than Psensor in well-functioning adults [mean difference = -0.31 W/kg and -0.22 W/kg for men and women, respectively (p < 0.001)], but not among limited-functioning older adults. To conclude, this study showed that age and functional limitations have an influence on the movement strategy during a 5-repetition STS test. Differences in movement strategy can affect the comparison between Pformula and Psensor. In well-functioning older adults, Pformula was slightly higher than Psensor, which might be related to an incomplete extension in the sit-to-stand transition.

Regulation of the endocannabinoid system by endurance and resistance exercise in hypoxia in human skeletal muscle.

Exercise modulates the circulating levels of the endocannabinoids ligands N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and possibly the levels of their receptors and downstream signaling in skeletal muscle. The aim of the present study was to investigate the regulation of the endocannabinoid system by several exercise paradigms in human skeletal muscle. A second aim was to compare endocannabinoid regulation in healthy and prediabetic people in response to an acute endurance exercise. Blood and muscle samples were taken before and after resistance and endurance exercise in normoxia and hypoxia to measure plasma endocannabinoid levels as well as muscle protein expression of CB1, CB2, and downstream signaling. We found that: 1) an acute resistance exercise session decreased plasma 2-AG and N-palmitoylethanolamine (PEA) levels in normoxia; 2) 4 wk resistance training decreased plasma AEA, PEA, and N-oleoylethanolamine (OEA) levels in both normoxia and hypoxia; 3) an acute moderate-intensity endurance exercise increased plasma OEA levels in the healthy and prediabetic groups in normoxia and hypoxia, whereas plasma 2-AG levels increased in the healthy group and AEA in the prediabetic group only in normoxia. The expression of the cannabinoid receptors was only marginally regulated by acute exercise, hypoxia, and prediabetes and downstream signaling did not follow the changes detected in the endocannabinoid ligands. Altogether, our results suggest that resistance and endurance exercise regulate the levels of the endocannabinoid ligands and CB1 expression in opposite ways. The physiological impact of the changes observed in the endocannabinoid ligands in human skeletal muscle after exercise needs further investigation.NEW & NOTEWORTHY We are the first to analyze both endocannabinoids ligands and receptors in response to endurance and resistance exercise. In addition, no study before has compared both exercise paradigms regarding endocannabinoid tone, which is of interest as endocannabinoids regulate energy metabolism, and these are different between endurance and resistance exercise. Furthermore, we investigated whether the endocannabinoid tone was differently regulated in response to acute endurance exercise in prediabetic people. Linking exercise, endocannabinoids and (pre)diabetic people has never been done before.

The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model.

Cannabinoid receptor 1 (CB1) antagonists were shown to stimulate in vitro muscle protein synthesis, but this has never been confirmed in vivo. Therefore, this study investigated whether treatment with the CB1 antagonist AM6545 upregulates in vivo muscle anabolism. Chronic AM6545 treatment stimulated the Akt-mTOR axis and protein synthesis (+22%; p = 0.002) in the Tibialis Anterior, which protected mice from dexamethasone-induced muscle loss (-1% vs. -6% compared to healthy controls; p = 0.02). Accordingly, acute AM6545 treatment stimulated protein synthesis (+44%; p = 0.04) in the Tibialis Anterior but not Soleus. The anabolic upregulation was accompanied by ERK1/2 activation, whereas protein kinase A signaling remained unaffected, suggesting a CB1-independent mechanism. The present study for the first time shows that the CB1 antagonist AM6545 can upregulate the Akt-mTOR axis and in vivo muscle protein synthesis. However, future work applying genetic approaches should further uncover the signaling pathways via which AM6545 enhances muscle anabolism.

Cannabidiol and brain function: current knowledge and future perspectives.

Cannabidiol (CBD) is a naturally occurring non-psychoactive cannabinoid found in Cannabis sativa, commonly known as cannabis or hemp. Although currently available CBD products do not meet the safety standards of most food safety authorities to be approved as a dietary supplement or food additive, CBD has been gaining widespread attention in recent years due to its various potential health benefits. While primarily known for its therapeutic effects in managing epileptic seizures, psychosis, anxiety, (neuropathic) pain, and inflammation, CBD's influence on brain function has also piqued the interest of researchers and individuals seeking to enhance cognitive performance. The primary objective of this review is to gather, synthesize, and consolidate scientifically proven evidence on the impact of CBD on brain function and its therapeutic significance in treating neurological and mental disorders. First, basic background information on CBD, including its biomolecular properties and mechanisms of action is presented. Next, evidence for CBD effects in the human brain is provided followed by a discussion on the potential implications of CBD as a neurotherapeutic agent. The potential effectiveness of CBD in reducing chronic pain is considered but also in reducing the symptoms of various brain disorders such as epilepsy, Alzheimer's, Huntington's and Parkinson's disease. Additionally, the implications of using CBD to manage psychiatric conditions such as psychosis, anxiety and fear, depression, and substance use disorders are explored. An overview of the beneficial effects of CBD on aspects of human behavior, such as sleep, motor control, cognition and memory, is then provided. As CBD products remain largely unregulated, it is crucial to address the ethical concerns associated with their use, including product quality, consistency, and safety. Therefore, this review discusses the need for responsible research and regulation of CBD to ensure its safety and efficacy as a therapeutic agent for brain disorders or to stimulate behavioral and cognitive abilities of healthy individuals.

Molecular Mechanisms Through Which Cannabidiol May Affect Skeletal Muscle Metabolism, Inflammation, Tissue Regeneration, and Anabolism: A Narrative Review.

Background: Cannabidiol (CBD), a nonintoxicating constituent of the cannabis plant, recently gained a lot of interest among athletes, since it is no longer considered as a prohibited substance by the World Anti-Doping Agency. The increasing prevalence of CBD use among athletes is driven by a perceived improvement in muscle recovery and a reduction in pain. However, compelling evidence from intervention studies is lacking and the precise mechanisms through which CBD may improve muscle recovery remain unknown. This highlights the need for more scientific studies and an evidence-based background. In the current review, the state-of-the-art knowledge on the effects of CBD on skeletal muscle tissue is summarized with special emphasis on the underlying mechanisms and molecular targets. More specifically, the large variety of receptor families that are believed to be involved in CBD's physiological effects are discussed. Furthermore, in vivo and in vitro studies that investigated the actual effects of CBD on skeletal muscle metabolism, inflammation, tissue regeneration, and anabolism are summarized, together with the functional effects of CBD supplementation on muscle recovery in human intervention trials. Overall, CBD was effective to increase the expression of metabolic regulators in muscle of obese mice (e.g., Akt, glycogen synthase kinase-3). CBD treatment in rodents reduced muscle inflammation following eccentric exercise (i.e., nuclear factor kappa B [NF-κB]), in a model of muscle dystrophy (e.g., interleukin-6, tumor necrosis factor alpha) and of obesity (e.g., COX-2, NF-κB). In addition, CBD did not affect in vitro or in vivo muscle anabolism, but improved satellite cell differentiation in dystrophic muscle. In humans, there are some indications that CBD supplementation improved muscle recovery (e.g., creatine kinase) and performance (e.g., squat performance). However, CBD doses were highly variable (between 16.7 and 150 mg) and there are some methodological concerns that should be considered. Conclusion: CBD has the prospective to become an adequate supplement that may improve muscle recovery. However, this research domain is still in its infancy and future studies addressing the molecular and functional effects of CBD in response to exercise are required to further elucidate the ergogenic potential of CBD.

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity.

The cannabinoid system is ubiquitously present and is classically considered to engage in neural and immunity processes. Yet, the role of the cannabinoid system in the whole body and tissue metabolism via central and peripheral mechanisms is increasingly recognized. The present review provides insights in (i) how cannabinoid signaling is regulated via receptor-independent and -dependent mechanisms and (ii) how these signaling cascades (might) affect skeletal muscle plasticity and physiology. Receptor-independent mechanisms include endocannabinoid metabolism to eicosanoids and the regulation of ion channels. Alternatively, endocannabinoids can act as ligands for different classic (cannabinoid receptor 1 [CB1 ], CB2 ) and/or alternative (e.g., TRPV1, GPR55) cannabinoid receptors with a unique affinity, specificity, and intracellular signaling cascade (often tissue-specific). Antagonism of CB1 might hold clues to improve oxidative (mitochondrial) metabolism, insulin sensitivity, satellite cell growth, and muscle anabolism, whereas CB2 agonism might be a promising way to stimulate muscle metabolism and muscle cell growth. Besides, CB2 ameliorates muscle regeneration via macrophage polarization toward an anti-inflammatory phenotype, induction of MyoD and myogenin expression and antifibrotic mechanisms. Also TRPV1 and GPR55 contribute to the regulation of muscle growth and metabolism. Future studies should reveal how the cannabinoid system can be targeted to improve muscle quantity and/or quality in conditions such as ageing, disease, disuse, and metabolic dysregulation, taking into account challenges that are inherent to modulation of the cannabinoid system, such as central and peripheral side effects.

Mechanosensors control skeletal muscle mass, molecular clocks, and metabolism.

BACKGROUND: Skeletal muscles (SkM) are mechanosensitive, with mechanical unloading resulting in muscle-devastating conditions and altered metabolic properties. However, it remains unexplored whether these atrophic conditions affect SkM mechanosensors and molecular clocks, both crucial for their homeostasis and consequent physiological metabolism. METHODS: We induced SkM atrophy through 14 days of hindlimb suspension (HS) in 10 male C57BL/6J mice and 10 controls (CTR). SkM histology, gene expressions and protein levels of mechanosensors, molecular clocks and metabolism-related players were examined in the m. Gastrocnemius and m. Soleus. Furthermore, we genetically reduced the expression of mechanosensors integrin-linked kinase (Ilk1) and kindlin-2 (Fermt2) in myogenic C2C12 cells and analyzed the gene expression of mechanosensors, clock components and metabolism-controlling genes. RESULTS: Upon hindlimb suspension, gene expression levels of both core molecular clocks and mechanosensors were moderately upregulated in m. Gastrocnemius but strongly downregulated in m. Soleus. Upon unloading, metabolism- and protein biosynthesis-related genes were moderately upregulated in m. Gastrocnemius but downregulated in m. Soleus. Furthermore, we identified very strong correlations between mechanosensors, metabolism- and circadian clock-regulating genes. Finally, genetically induced downregulations of mechanosensors Ilk1 and Fermt2 caused a downregulated mechanosensor, molecular clock and metabolism-related gene expression in the C2C12 model. CONCLUSIONS: Collectively, these data shed new lights on mechanisms that control muscle loss. Mechanosensors are identified to crucially control these processes, specifically through commanding molecular clock components and metabolism.

Preliminary Evidence of Differential Expression of Myogenic and Stress Factors in Skeletal Muscle of Older Adults With Low Muscle Strength.

The age-related loss of muscle strength and mass, or sarcopenia, is a growing concern in the aging population. Yet, it is not fully understood which molecular mechanisms underlie sarcopenia. Therefore, the present study compared the protein expression profile, such as catabolic, oxidative, stress-related, and myogenic pathways, between older adults with preserved (8 ♀ and 5 ♂; 71.5 ± 2.6 years) and low muscle strength (6 ♀ and 5 ♂; 78.0 ± 5.0 years). Low muscle strength was defined as chair stand test time more than 15 seconds and/or handgrip strength less than 16 kg (women) or less than 27 kg (men) according to the EWGSOP2 criteria. Catabolic signaling (ie, FOXO1/3a, MuRF1, MAFbx, LC3b, Atg5, p62) was not differentially expressed between both groups, whereas the mitochondrial marker COX-IV, but not PGC1α and citrate synthase, was lower in the low muscle strength group. Stress factors CHOP and p-ERK1/2 were higher (~1.5-fold) in older adults with low muscle strength. Surprisingly, the inflammatory marker p-p65NF-κB was ~7-fold higher in older adults with preserved muscle strength. Finally, expression of myogenic factors (ie, Pax7, MyoD, desmin; ~2-fold) was higher in adults with low muscle strength. To conclude, whereas the increased stress factors might reflect the age-related deterioration of tissue homeostasis, for example, due to misfolded proteins (CHOP), upregulation of myogenic markers in the low strength group might be an attempt to compensate for the gradual loss in muscle quantity and quality. These data might provide valuable insights into the processes that underlie sarcopenia.

Sodium bicarbonate improves sprint performance in endurance cycling.

OBJECTIVES: Oral sodium bicarbonate intake (NaHCO3) may improve performance in short maximal exercise by inducing metabolic alkalosis. However, it remains unknown whether NaHCO3 also enhances all-out performance at the end of an endurance competition. Therefore, the present study investigated the effect of stacked NaHCO3 loading on sprint performance following a 3-h simulated cycling race. DESIGN: Double-blind randomized placebo-controlled cross-over study. METHODS: Eleven trained male cyclists (22.3 (18.3-25.3) year; 73.0 (61.5-88) kg; VO2max: 63.7 (57-72) mlkg-1min-1) ingested either 300mgkg-1 body weight NaHCO3 (BIC) or NaCl (PL). NaHCO3 or NaCl was supplemented prior to (150mgkg-1) and during (150mgkg-1) a 3-h simulated cycling race with a 90-s all-out sprint (90S) at the end. Capillary blood samples were collected for determination of blood pH, lactate and HCO3- concentrations. Analysis of variance (lactate, pH, HCO3-) and paired t-test (power) were applied to compare variables across condition (and time). RESULTS: NaHCO3 intake improved mean power during 90S by ∼3% (541±59W vs. 524±57W in PL, p=0.047, Cohen's D=0.28, medium). Peak blood lactate concentration and heart rate at the end of 90S were higher (p<0.05) in BIC (16.2±4.1mmoll1, 184±7bpm) than in PL (12.4±4.2mmoll-1, 181±5bpm). NaHCO3 ingestion increased blood [HCO3-] (31.5±1.3 vs. 24.4±1.5mmoll-1 in PL, p<0.001) and blood pH (7.50±0.01 vs. 7.41±0.03 in PL, p<0.05) prior to 90S. CONCLUSIONS: NaHCO3 supplementation prior and during endurance exercise improves short all-out exercise performance at the end of the event. Therefore, sodium bicarbonate intake can be applied as a strategy to increase success rate in endurance competitions.

Adaptations in Reactive Balance Strategies in Healthy Older Adults After a 3-Week Perturbation Training Program and After a 12-Week Resistance Training Program.

Both resistance training (RT) and perturbation-based training (PBT) have been proposed and applied as interventions to improve reactive balance performance in older adults. PBT is a promising approach but the adaptations in underlying balance-correcting mechanisms through which PBT improves reactive balance performance are not well-understood. Besides it is unclear whether PBT induces adaptations that generalize to movement tasks that were not part of the training and whether those potential improvements would be larger than improvements induced by RT. We performed two training interventions with two groups of healthy older adults: a traditional 12-week RT program and a 3-week PBT program consisting of support-surface perturbations of standing balance. Reactive balance performance during standing and walking as well as a set of neuro-muscular properties to quantify muscle strength, sensory and motor acuity, were assessed pre- and post-intervention. We found that both PBT and RT induced training specific improvements, i.e., standing PBT improved reactive balance during perturbed standing and RT increased strength, but neither intervention affected reactive balance performance during perturbed treadmill walking. Analysis of the reliance on different balance-correcting strategies indicated that specific improvements in the PBT group during reactive standing balance were due to adaptations in the stepping threshold. Our findings indicate that the strong specificity of PBT can present a challenge to transfer improvements to fall prevention and should be considered in the design of an intervention. Next, we found that lack of improvement in muscle strength did not limit improving reactive balance in healthy older adults. For improving our understanding of generalizability of specific PBT in future research, we suggest performing an analysis of the reliance on the different balance-correcting strategies during both the training and assessment tasks.

Cannabinoid receptor 1 expression is higher in muscle of old vs. young males, and increases upon resistance exercise in older adults.

Aged skeletal muscle undergoes metabolic and structural alterations eventually resulting in a loss of muscle strength and mass, i.e. age-related sarcopenia. Therefore, novel targets for muscle growth purposes in elderly are needed. Here, we explored the role of the cannabinoid system in muscle plasticity through the expression of muscle cannabinoid receptors (CBs) in young and old humans. The CB1 expression was higher (+ 25%; p = 0.04) in muscle of old (≥ 65 years) vs. young adults (20-27 years), whereas CB2 was not differently expressed. Furthermore, resistance exercise tended to increase the CB1 (+ 11%; p = 0.055) and CB2 (+ 37%; p = 0.066) expression in muscle of older adults. Interestingly, increases in the expression of CB2 following resistance exercise positively correlated with changes in key mechanisms of muscle homeostasis, such as catabolism (FOXO3a) and regenerative capacity (Pax7, MyoD). This study for the first time shows that CB1 is differentially expressed with aging and that changes in CB2 expression upon resistance exercise training correlate with changes in mediators that play a central role in muscle plasticity. These data confirm earlier work in cells and mice showing that the cannabinoid system might orchestrate muscle growth, which is an incentive to further explore CB-based strategies that might counteract sarcopenia.

Voluntary exercise does not improve muscular properties or functional capacity during C26-induced cancer cachexia in mice.

Exercise training is considered as a potential intervention to counteract muscle degeneration in cancer cachexia. However, evidence to support such intervention is equivocal. Therefore, we investigated the effect of exercise training, i.e. voluntary wheel running, on muscle wasting, functional capacity, fiber type composition and vascularization during experimental cancer cachexia in mice. Balb/c mice were injected with PBS (CON) or C26 colon carcinoma cells to induce cancer cachexia (C26). Mice had free access to a running wheel in their home cage (CONEX and C26EX, n = 8-9) or were sedentary (CONS and C26S, n = 8-9). Mice were sacrificed 18 days upon tumor cell injection. Immunohistochemical analyes were performed on m. gastrocnemius and quadriceps, and ex vivo contractile properties were assessed in m. soleus and extensor digitorum longus (EDL). Compared with CON, C26 mice exhibited body weight loss (~ 20 %), muscle atrophy (~ 25 %), reduced grip strength (~ 25 %), and lower twitch and tetanic force (~ 20 %) production in EDL but not in m. soleus. Furthermore, muscle of C26 mice were characterizd by a slow-to-fast fiber type shift (type IIx fibers: +57 %) and increased capillary density (~ 30 %). In C26 mice, wheel running affect neither body weight loss, nor muscle atrophy or functional capacity, nor inhibited tumor growth. However, wheel running induced a type IIb to type IIa fiber shift in m. quadriceps from both CON and C26, but not in m. gastrocnemius. Wheel running does not exacerbate muscular degeneration in cachexic mice, but, when voluntary, is insufficient to improve the muscle phenotype.

Omega-3 Supplementation Improves Isometric Strength But Not Muscle Anabolic and Catabolic Signaling in Response to Resistance Exercise in Healthy Older Adults.

Old skeletal muscle exhibits decreased anabolic sensitivity, eventually contributing to muscle wasting. Besides anabolism, also muscle inflammation and catabolism are critical players in regulating the old skeletal muscle's sensitivity. Omega-3 fatty acids (ω-3) are an interesting candidate to reverse anabolic insensitivity via anabolic actions. Yet, it remains unknown whether ω-3 also attenuates muscle inflammation and catabolism. The present study investigates the effect of ω-3 supplementation on muscle inflammation and metabolism (anabolism/catabolism) upon resistance exercise (RE). Twenty-three older adults (65-84 years; 8♀) were randomized to receive ω-3 (~3 g/d) or corn oil (placebo [PLAC]) and engaged in a 12-week RE program (3×/wk). Before and after intervention, muscle volume, strength, and systemic inflammation were assessed, and muscle biopsies were analyzed for markers of anabolism, catabolism, and inflammation. Isometric knee-extensor strength increased in ω-3 (+12.2%), but not in PLAC (-1.4%; pinteraction = .015), whereas leg press strength improved in both conditions (+27.1%; ptime < .001). RE, but not ω-3, decreased inflammatory (p65NF-κB) and catabolic (FOXO1, LC3b) markers, and improved muscle quality. Yet, muscle volume remained unaffected by RE and ω-3. Accordingly, muscle anabolism (mTORC1) and plasma C-reactive protein remained unchanged by RE and ω-3, whereas serum IL-6 tended to decrease in ω-3 (pinteraction = .07). These results show that, despite no changes in muscle volume, RE-induced gains in isometric strength can be further enhanced by ω-3. However, ω-3 did not improve RE-induced beneficial catabolic or inflammatory adaptations. Irrespective of muscle volume, gains in strength (primary criterion for sarcopenia) might be explained by changes in muscle quality due to muscle inflammatory or catabolic signaling.

Cardiotoxin-induced skeletal muscle injury elicits profound changes in anabolic and stress signaling, and muscle fiber type composition.

To improve muscle healing upon injury, it is of importance to understand the interplay of key signaling pathways during muscle regeneration. To study this, mice were injected with cardiotoxin (CTX) or PBS in the Tibialis Anterior muscle and were sacrificed 2, 5 and 12 days upon injection. The time points represent different phases of the regeneration process, i.e. destruction, repair and remodeling, respectively. Two days upon CTX-injection, p-mTORC1 signaling and stress markers such as BiP and p-ERK1/2 were upregulated. Phospho-ERK1/2 and p-mTORC1 peaked at d5, while BiP expression decreased towards PBS levels. Phospho-FOXO decreased 2 and 5 days following CTX-injection, indicative of an increase in catabolic signaling. Furthermore, CTX-injection induced a shift in the fiber type composition, characterized by an initial loss in type IIa fibers at d2 and at d5. At d5, new type IIb fibers appeared, whereas type IIa fibers were recovered at d12. To conclude, CTX-injection severely affected key modulators of muscle metabolism and histology. These data provide useful information for the development of strategies that aim to improve muscle molecular signaling and thereby recovery.