Methylglyoxal reduces molecular responsiveness to 4 weeks of endurance exercise in mouse plantaris muscle

Endurance exercise triggers skeletal muscle adaptations, including enhanced insulin signaling, glucose metabolism, and mitochondrial biogenesis. However, exercise-induced skeletal muscle adaptations may not occur in some cases, a condition known as exercise-resistance. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite and has detrimental effects on the body such as causing diabetic complications, mitochondrial dysfunction, and inflammation. This study aimed to clarify the effect of methylglyoxal on skeletal muscle molecular adaptations following endurance exercise. Mice were randomly divided into 4 groups (n = 12 per group): sedentary control group, voluntary exercise group, MG-treated group, and MG-treated with voluntary exercise group. Mice in the voluntary exercise group were housed in a cage with a running wheel, while mice in the MG-treated groups received drinking water containing 1% MG. Four weeks of voluntary exercise induced several molecular adaptations in the plantaris muscle, including increased expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), mitochondria complex proteins, toll-like receptor 4 (TLR4), 72-kDa heat shock protein (HSP72), hexokinase II, and glyoxalase 1; this also enhanced insulin-stimulated Akt Ser473 phosphorylation and citrate synthase activity. However, these adaptations were suppressed with MG treatment. In the soleus muscle, the exercise-induced increases in the expression of TLR4, HSP72, and advanced glycation end products receptor 1 were inhibited with MG treatment. These findings suggest that MG is a factor that inhibits endurance exercise-induced molecular responses including mitochondrial adaptations, insulin signaling activation, and the upregulation of several proteins related to mitochondrial biogenesis, glucose handling, and glycation in primarily fast-twitch skeletal muscle.

Implication of satellite cell behaviors in capillary growth via VEGF expression-independent mechanism in response to mechanical loading in HeyL-null mice

Angiogenesis and muscle satellite cell (SC)-mediated myonuclear accretion are considered essential for the robust response of contraction-induced muscle hypertrophy. Moreover, both myonucleus and SCs are physically adjacent to capillaries and are the major sites for the expression of proangiogenic factors, such as VEGF, in the skeletal muscle. Thus, events involving the addition of new myonuclei via activation of SCs may play an important role in angiogenesis during muscle hypertrophy. However, the relevance among myonuclei number, capillary density, and angiogenesis factor is not demonstrated. The Notch effector HeyL is specifically expressed in SCs in skeletal muscle and is crucial for SC proliferation by inhibiting MyoD in overload-induced muscle hypertrophy. Here, we tested whether the addition of new myonuclei by SC in overloaded muscle is associated with angiogenic adaptation by reanalyzing skeletal muscle from HeyL knockout (KO) mice, which show blunted responses of SC proliferation, myonucleus addition, and overload-induced muscle hypertrophy. Reanalysis confirmed blunted SC proliferation and myonuclear accretion in the plantaris muscle of HeyL-KO mice 9 weeks after synergist ablation. Interestingly, the increase in capillary-fiber ratio observed in WT mice was impaired in HeyL-KO mice. In both WT and HeyL-KO mice, the expression of VEGFA and VEGFB was similarly increased in response to overload. In addition, the expression pattern of TSP-1, a negative regulator of angiogenesis, was also not changed between WT and HeyL-KO mice. Collectively, these results suggest that SCs activation-myonuclear accretion plays a crucial role in angiogenesis during overload-induced muscle hypertrophy via independent of angiogenesis regulators.

Identification of driver genes and biological signaling for alcoholic myopathy

Long-term alcohol consumption contributes to muscle weakness and atrophy. However, the mechanism and biological functions are still not clear. In this study, we aim to identify the significantly changed genes and potential signaling pathways in the gastrocnemius and plantaris muscle from C57BL/6Hsd mice by analyzing RNA sequence. The GSE183665 dataset was created by using the Illumina NovaSeq 6000 (Mus musculus). The KEGG and GO analyses showed that "cell migration", "cell adhesion", and "apoptosis" are major biological processes in the skeletal muscles. Moreover, we identified a number of genes including POSTN, GNAI2, MMP2, ELN, CCND1, CXCL12, COL6A1, COL6A2, SFRP2, and FSTL1 by using the PPI network and Reactome map. Thus, our study may shed light on the development of drugs on alcohol myopathy.

Impact of Exercise and Detraining during Childhood on Brown Adipose Tissue Whitening in Obesity

This study aimed to investigate the influence of childhood exercise and detraining on brown adipose tissue (BAT) whitening in obesity. Four-week-old male Long-Evans Tokushima Otsuka (LETO) rats (n = 9) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 24) were used as non-obese and obese animals, respectively. OLETF rats were divided into non-exercise sedentary (n = 9) and exercise groups. OLETF rats in the exercise group were further divided into subgroups according to the exercise period—exercise from 10- to 12-weeks-old (n = 6); and exercise from 4- to 6-weeks-old, and detraining from 6- to 12-weeks-old (n = 9). At 12-weeks-old, immediately after exercise period, BAT whitening in OLETF rats was inhibited by exercise despite the fact that hypertrophy was not caused in the plantaris muscle. However, the effectiveness was attenuated during the detraining period. Histological BAT whitening and downregulation of uncoupling protein-1 (UCP-1) were found in non-exercise sedentary OLETF rats at 12-weeks-old. The downregulation was not inhibited, even though exercise histologically inhibited BAT whitening in OLETF rats. Childhood exercise decreased BAT whitening in obesity. Detraining attenuated the inhibition of BAT whitening. These results suggest that regular exercise is needed to improve BAT whitening and downregulation of UCP-1 in obesity.

Morphological variability of the plantaris tendon in the human fetus

Muscular anatomy often differs between species and individuals. In particular, the plantaris muscle (PM) demonstrates great morphological variability in its course and its proximal and distal attachments. The aim of this study was to investigate the morphological variation of the PM tendon in human fetuses. Forty-six spontaneously aborted human fetuses (23 male, 23 female) aged 18–38 weeks of gestation were studied. Morphology of the attachment of the PM was assessed in both lower extremities (n = 92). The PM was present in 72 lower limbs (78.26%) and absent in 20 (21.74%). Eight types of PM distal attachment were identified. We propose an eight-fold classification of PM insertion in fetuses. Leg length, length of tendon, extension point (ExP) from the calcaneus, and ExP thickness differed significantly among types of PM insertion.

Functional Popliteal Artery Entrapment Syndrome: An Approach to Diagnosis and Management

Popliteal Artery Entrapment Syndrome (PAES) is an uncommon syndrome that predominantly affects young athletes. Functional PAES is a subtype of PAES without anatomic entrapment of the popliteal artery. Patients with functional PAES tend to be younger and more active than typical PAES patients. A number of differential diagnoses exist, the most common of which is chronic exertional compartment syndrome. There is no consensus regarding choice of investigation for these patients. However, exercise ankle-brachial indices and magnetic resonance imaging are less invasive alternatives to digital subtraction angiography. Patients with typical symptoms that are severe and repetitive should be considered for intervention. Surgical intervention consists of release of the popliteal artery, either via a posterior or medial approach. The Turnipseed procedure involves a medial approach with a concomitant release of the medial gastrocnemius and soleal fascia, the medial tibial attachments of the soleus and excision of the proximal third of the plantaris muscle. Injection of botulinum A toxin under electromyographic guidance has recently shown promise as a diagnostic and/or therapeutic intervention in small case series. This review provides relevant information for the clinician investigating and managing patients with functional PAES.

Hypertrophy of Rat Skeletal Muscle Is Associated with Increased SIRT1/Akt/mTOR/S6 and Suppressed Sestrin2/SIRT3/FOXO1 Levels

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.

Absence of Desmin Results in Impaired Adaptive Response to Mechanical Overloading of Skeletal Muscle

Background: Desmin is a muscle-specific protein belonging to the intermediate filament family. Desmin mutations are linked to skeletal muscle defects, including inherited myopathies with severe clinical manifestations. The aim of this study was to examine the role of desmin in skeletal muscle remodeling and performance gain induced by muscle mechanical overloading which mimics resistance training.Methods: Plantaris muscles were overloaded by surgical ablation of gastrocnemius and soleus muscles. The functional response of plantaris muscle to mechanical overloading in desmin-deficient mice (DesKO, n = 32) was compared to that of control mice (n = 36) after 7-days or 1-month overloading. To elucidate the molecular mechanisms implicated in the observed partial adaptive response of DesKO muscle, we examined the expression levels of genes involved in muscle growth, myogenesis, inflammation and oxidative energetic metabolism. Moreover, ultrastructure and the proteolysis pathway were explored.Results: Contrary to control, absolute maximal force did not increase in DesKO muscle following 1-month mechanical overloading. Fatigue resistance was also less increased in DesKO as compared to control muscle. Despite impaired functional adaptive response of DesKO mice to mechanical overloading, muscle weight and the number of oxidative MHC2a-positive fibers per cross-section similarly increased in both genotypes after 1-month overloading. However, mechanical overloading-elicited remodeling failed to activate a normal myogenic program after 7-days overloading, resulting in proportionally reduced activation and differentiation of muscle stem cells. Ultrastructural analysis of the plantaris muscle after 1-month overloading revealed muscle fiber damage in DesKO, as indicated by the loss of sarcomere integrity and mitochondrial abnormalities. Moreover, the observed accumulation of autophagosomes and lysosomes in DesKO muscle fibers could indicate a blockage of autophagy. To address this issue, two main proteolysis pathways, the ubiquitin-proteasome system and autophagy, were explored in DesKO and control muscle. Our results suggested an alteration of proteolysis pathways in DesKO muscle in response to mechanical overloading.Conclusion: Taken together, our results show that mechanical overloading increases the negative impact of the lack of desmin on myofibril organization and mitochondria. Furthermore, our results suggest that under these conditions, the repairing activity of autophagy is disturbed. Consequently, force generation is not improved despite muscle growth, suggesting that desmin is required for a complete response to resistance training in skeletal muscle.

The combination of smoking with vitamin D deficiency impairs skeletal muscle fiber hypertrophy in response to overload in mice

Vitamin D deficiency, which is highly prevalent in the general population, exerts similar deleterious effects on skeletal muscles to those induced by cigarette smoking. We examined whether cigarette smoke (CS) exposure and/or vitamin D deficiency impairs the skeletal muscle hypertrophic response to overload. Male C57Bl/6JolaH mice on a normal or vitamin D-deficient diet were exposed to CS or room air for 18 weeks. Six weeks after initiation of CS or air exposure, sham surgery or denervation of the agonists of the left plantaris muscle was performed. The right leg served as internal control. Twelve weeks later, the hypertrophic response was assessed. CS exposure instigated loss of body and muscle mass, and increased lung inflammatory cell infiltration (p<0.05), independently of diet. Maximal exercise capacity, whole body strength, in situ plantaris muscle force and key markers of hypertrophic signaling (Akt, 4EBP1, FoxO1) were not significantly affected by smoking or diet. The increase in plantaris muscle fiber cross-sectional area in response to overload was attenuated in vitamin D-deficient CS-exposed mice (smoking x diet interaction for hypertrophy, p=0.03). In situ fatigue resistance was elevated in hypertrophied plantaris, irrespective of vitamin D deficiency and/or CS exposure. In conclusion, our data show that CS exposure or vitamin D deficiency alone did not attenuate the hypertrophic response of overloaded plantaris muscles, but this hypertrophic response was weakened when both conditions were combined. These data suggest that current smokers who also present with vitamin D deficiency may be less likely to respond to a training program.