PGC-1α coactivator plays a decisive role in the maintenance of lipid balance via engagement in numerous metabolic processes (i.e., Krebs cycle, β-oxidation, oxidative phosphorylation and electron transport chain). It constitutes a link between fatty acids import and their complete oxidation or conversion into bioactive fractions through the coordination of both the expression and subcellular relocation of the proteins involved in fatty acid transmembrane movement. Studies on cell lines and/or animal models highlighted the existence of an upregulation of the total and mitochondrial FAT/CD36, FABPpm and FATPs content in skeletal muscle in response to PGC-1α stimulation. On the other hand, the association between PGC-1α level or activity and the fatty acids transport in the heart and adipocytes is still elusive. So far, the effects of PGC-1α on the total and sarcolemmal expression of FAT/CD36, FATP1, and FABPpm in cardiomyocytes have been shown to vary in relation to the type of PPAR that was coactivated. In brown adipose tissue (BAT) PGC-1α knockdown was linked with a decreased level of lipid metabolizing enzymes and fatty acid transporters (FAT/CD36, FABP3), whereas the results obtained for white adipose tissue (WAT) remain contradictory. Furthermore, dysregulation in lipid turnover is often associated with insulin intolerance, which suggests the coactivator's potential role as a therapeutic target.

Muscle fatigue is defined as a decrease in maximal force or power generated in response to contractile activity, and it is a risk factor for the development of musculoskeletal injuries. One of the many stressors imposed on skeletal muscle through exercise is the increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which intensifies as a function of exercise intensity and duration. Exposure to ROS/RNS can affect Na⁺/K⁺-ATPase activity, intramyofibrillar calcium turnover and sensitivity, and actin–myosin kinetics to reduce muscle force production. On the other hand, low ROS/RNS concentrations can likely upregulate an array of cellular adaptative responses related to mitochondrial biogenesis, glucose transport and muscle hypertrophy. Consequently, growing evidence suggests that exogenous antioxidant supplementation might hamper exercise-engendering upregulation in the signaling pathways of mitogen-activated protein kinases (MAPKs), peroxisome-proliferator activated co-activator 1α (PGC-1α), or mammalian target of rapamycin (mTOR). Ultimately, both high (exercise-induced) and low (antioxidant intervention) ROS concentrations can trigger beneficial responses as long as they do not override the threshold range for redox balance. The mechanisms underlying the two faces of ROS/RNS in exercise, as well as the role of antioxidants in muscle fatigue, are presented in detail in this review.

Branched chain amino acids (BCAA) and their derivatives are bioactive molecules with pleiotropic functions in the human body. Elevated fasting blood BCAA concentrations are considered as a metabolic hallmark of obesity, insulin resistance, dyslipidaemia, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease. However, since increased BCAA amount is observed both in metabolically healthy and obese subjects, a question whether BCAA are mechanistic drivers of insulin resistance and its morbidities or only markers of metabolic dysregulation, still remains open. The beneficial effects of BCAA on body weight and composition, aerobic capacity, insulin secretion and sensitivity demand high catabolic potential toward amino acids and/or adequate BCAA intake. On the opposite, BCAA-related inhibition of lipogenesis and lipolysis enhancement may preclude impairment in insulin sensitivity. Thereby, the following review addresses various strategies pertaining to the modulation of BCAA catabolism and the possible roles of BCAA in energy homeostasis. We also aim to elucidate mechanisms behind the heterogeneity of ramifications associated with BCAA modulation.

Ovarian cancer is a non-homogenous malignancy. High-grade serous carcinoma (HGSC) is the most common subtype, and its drug resistance mechanisms remain unclear. Despite the advantages of modern pharmacotherapy, high-grade ovarian cancer is associated with a poor prognosis and research into targeted therapies is in progress. The aim of the study was to assess the dominant energy substrate transport mechanism in ovarian cancer cells and to verify whether genomic aberrations could predict clinical outcomes using the Cancer Genome Atlas (TCGA) dataset. Total RNA was extracted from HGSC frozen tissues, and the expression of selected genes was compared to respective controls. GLUT1, FABPpm, MCT4 and SNAT1 genes were significantly overexpressed in carcinomas compared with controls, while expression of CD36/SR-B2, FATP1, FABP4, GLUT4, ASCT2 and LPL was decreased. No differences were found in FATP4, LAT1, MCT1 and FASN. The transcript content of mitochondrial genes such as PGC-1α, TFAM and COX4/1 was similar between groups, while the β-HAD level declined in ovarian cancer. Additionally, the MCT4 level was reduced and PGC-1α was elevated in cancer tissue from patients with ‘small’ primary tumor and omental invasion accompanied by ascites as compared to patients that exhibited greater tendencies to metastasize to lymph nodes with clear omentum. Based on TCGA, higher FABP4 and LPL and lower TFAM expression indicated poorer overall survival in patients with ovarian cancer. In conclusion, the presented data show that there is no exclusive energy substrate in HGSC. However, this study indicates the advantage of glucose and lactate transport over fatty acids, thereby suggesting potential therapeutic intervention targets to impede ovarian cancer growth.

Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small amounts of myostatin are produced by the myocardium and the adipose tissue as well. Myostatin binds to activin IIB membrane receptors to activate the downstream intracellular canonical Smad2/Smad3 pathway, and additionally acts on non-Smad (non-canonical) pathways. Studies on transgenic animals have shown that overexpression of myostatin reduces the heart mass, whereas removal of myostatin has an opposite effect. In this review, we summarize the potential diagnostic and prognostic value of this protein in heart-related conditions. First, in myostatin-null mice the left ventricular internal diameters along with the diastolic and systolic volumes are larger than the respective values in wild-type mice. Myostatin is potentially secreted as part of a negative feedback loop that reduces the effects of the release of growth-promoting factors and energy reprogramming in response to hypertrophic stimuli. On the other hand, both human and animal data indicate that myostatin is involved in the development of the cardiac cachexia and heart fibrosis in the course of chronic heart failure. The understanding of the role of myostatin in such conditions might initiate a development of targeted therapies based on myostatin signaling inhibition.

TBC1D4 (AS160) and TBC1D1 are Rab GTPase-activating proteins that play a key role in the regulation of glucose and possibly the transport of long chain fatty acids (LCFAs) into muscle and fat cells. Knockdown (KD) of TBC1D4 increased CD36/SR-B2 and FABPpm protein expressions in L6 myotubes, whereas in murine cardiomyocytes, TBC1D4 deficiency led to a redistribution of CD36/SR-B2 to the sarcolemma. In our study, we investigated the previously unexplored role of both Rab-GAPs in LCFAs uptake in human adipocytes differentiated from the ADMSCs of subcutaneous and visceral adipose tissue origin. To this end we performed a single- and double-knockdown of the proteins (TBC1D1 and TBC1D4). Herein, we provide evidence that AS160 mediates fatty acid entry into the adipocytes derived from ADMSCs. TBC1D4 KD resulted in quite a few alterations to the cellular phenotype, the most obvious of which was the shift of the CD36/SR-B2 transport protein to the plasma membrane. The above translated into an increased uptake of saturated long-chain fatty acid. Interestingly, we observed a tissue-specific pattern, with more pronounced changes present in the adipocytes derived from subADMSCs. Altogether, our data show that in human adipocytes, TBC1D4, but not TBC1D1, deficiency increases LCFAs transport via CD36/SR-B2 translocation.