Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).

Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism

Engaging in regular exercise and physical activity contributes to delaying the onset of cardiovascular diseases (CVDs). However, the physiological mechanisms underlying the benefits of regular exercise or physical activity in CVDs remain unclear. The disruption of mitochondrial homeostasis is implicated in the pathological process of CVDs. Exercise training effectively delays the onset and progression of CVDs by significantly ameliorating the disruption of mitochondrial homeostasis. This includes improving mitochondrial biogenesis, increasing mitochondrial fusion, decreasing mitochondrial fission, promoting mitophagy, and mitigating mitochondrial morphology and function. This review provides a comprehensive overview of the benefits of physical exercise in the context of CVDs, establishing a connection between the disruption of mitochondrial homeostasis and the onset of these conditions. Through a detailed examination of the underlying molecular mechanisms within mitochondria, the study illuminates how exercise can provide innovative perspectives for future therapies for CVDs. 

Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis

The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway. 

Arginine Regulates Skeletal Muscle Fiber Type Formation via mTOR Signaling Pathway

Myokines are defined as a heterogenic group of numerous cytokines, peptides and metabolic derivates, which are expressed, synthesized, produced, and released by skeletal myocytes and myocardial cells and exert either auto- and paracrine, or endocrine effects. Previous studies revealed that myokines play a pivotal role in mutual communications between skeletal muscles, myocardium and remote organs, such as brain, vasculature, bone, liver, pancreas, white adipose tissue, gut, and skin. Despite several myokines exert complete divorced biological effects mainly in regulation of skeletal muscle hypertrophy, residential cells differentiation, neovascularization/angiogenesis, vascular integrity, endothelial function, inflammation and apoptosis/necrosis, attenuating ischemia/hypoxia and tissue protection, tumor growth and malignance, for other occasions, their predominant effects affect energy homeostasis, glucose and lipid metabolism, adiposity, muscle training adaptation and food behavior. Last decade had been identified 250 more myokines, which have been investigating for many years further as either biomarkers or targets for heart failure management. However, only few myokines have been allocated to a promising tool for monitoring adverse cardiac remodeling, ischemia/hypoxia-related target-organ dysfunction, microvascular inflammation, sarcopenia/myopathy and prediction for poor clinical outcomes among patients with HF. This we concentrate on some most plausible myokines, such as myostatin, myonectin, brain-derived neurotrophic factor, muslin, fibroblast growth factor 21, irisin, leukemia inhibitory factor, developmental endothelial locus-1, interleukin-6, nerve growth factor and insulin-like growth factor-1, which are suggested to be useful biomarkers for HF development and progression. 

Diagnostic and predictive abilities of myokines in patients with heart failure

It is unclear whether resistance training in combination with different timing of protein intake might have differential effects on muscle hypertrophy, strength, and performance. Therefore, we compared the effects of 8 weeks of resistance training combined with two different high-protein diet strategies (immediately pre-and after, or 3 h pre and after exercise) in resistance-trained males.Forty resistance-trained males (24 ± 4 years) performed 8 weeks of resistance training combined with 2 g kg−1 d−1 protein. Body composition, muscular performance, and biochemical markers were assessed pre and post-intervention.Nine participants (four from 3 h group and five from the immediate group) withdrew from the study. Therefore, 31 participants completed the study. All measures of skeletal muscle mass, Australian pull-up, and muscle strength, significantly increased post-intervention in both groups (p < 0.05). The biochemical marker urea also significantly increased from pre to post in both groups (p < 0.05). There were no significant between-group differences (p > 0.05).High-protein diet enhances muscular performance and skeletal muscle mass in resistance-trained males, irrespective of intake time. Consequently, the total daily protein intake appears to be the primary factor in facilitating muscle growth induced by exercise.

Timing matters? The effects of two different timing of high protein diets on body composition, muscular performance, and biochemical markers in resistance-trained males

Fgf21 has been identified as playing a regulatory role in muscle growth and function. Although the mechanisms through which endurance training regulates skeletal muscle have been widely studied, the contribution of Fgf21 remains poorly understood. Here, muscle size and function were measured, and markers of fiber type were evaluated using immunohistochemistry, immunoblots, or qPCR in endurance-exercise-trained wild-type and Fgf21 KO mice. We also investigated Fgf21-induced fiber conversion in C2C12 cells, which were incubated with lentivirus and/or pathway inhibitors. We found that endurance exercise training enhanced the Fgf21 levels of liver and GAS muscle and exercise capacity and decreased the distribution of skeletal muscle fiber size, and fast-twitch fibers were observed converting to slow-twitch fibers in the GAS muscle of mice. Fgf21 promoted the markers of fiber-type transition and eMyHC-positive myotubes by inhibiting the TGF-β1 signaling axis and activating the p38 MAPK signaling pathway without apparent crosstalk. Our findings suggest that the transformation and function of skeletal muscle fiber types in response to endurance training could be mediated by Fgf21 and its downstream signaling pathways. Our results illuminate the mechanisms of Fgf21 in endurance-exercise-induced fiber-type conversion and suggest a potential use of Fgf21 in improving muscle health and combating fatigue.

Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-β1 and p38 MAPK Signaling Pathway

Expression analysis of irisin during different development stages of skeletal muscle in mice.

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Endurance Exercise-Induced Fgf21 Promotes Skeletal Muscle Fiber Conversion through TGF-β1 and p38 MAPK Signaling Pathway

Expression analysis of irisin during different development stages of skeletal muscle in mice.