**10. Heat controls vital signaling molecules in plasma membrane**

have tendency to coalesce into larger platforms to form signalosomes essential for signal transduction [22]. Thus, in muscle cells deprived of mevalonate due to statin administration, one should expect lower level of LR/C and decreased availability of prenylated proteins (farnesylated and geranyl-geranylated). It is important to stress that muscle growth, adaptive hypertrophy, and regeneration are directly attributable to the PM representation of LR determined by CHOL and sphingolipids [87, 91] found in RSC. The mononucleated RSC are located beneath the basal lamina that surrounds multinucleated myofibers [6]. They are activated by signals from injured myofibers and macrophages to enter the cell cycle and produce myogenic precursor cells that then differentiate and fuse into multinucleated myotubes or existing myofibers [92]. The molecular mechanisms responsible for the trans‐ duction of such extracellular signals in satellite cells remain poorly defined, and the potential role of lipid-mediated signaling has not been previously considered in this context. There is an assumption that satellite cells are capable to rearrange PM composition in order to respond to extracellular signals and allow cell multiplication and migration which is followed by fusion. Actually, muscle cells were reported to change the lipid representation in PM according to the particular step of differentiation [87, 91, 93]. While phosphatidylserine (PS) is highly expressed during myoblast fusion [88], phosphatidylethanolamine (PE) is involved in cell motility [94]. Both mentioned are the glycerophospholipids of Ld phase located in the protoplasmic leaflet. On the other hand, sphingomyelin (SM) is found exclusively in the Lo phase where it forms LR nanodomains with other SL, GSL, CHOL, and proteins. CHOL is essential to organize LR as it helps both to position SL and GSL and provides the most advantageous energy status between Lo and Ld phase [95]. Nowadays, it is widely accepted that these nanodomains facilitate cytoplasmic signaling by acting to concentrate signaling molecules [96]. Additionally, SL metabolites, such as ceramide, sphingosine, and sphingosine 1-phosphate, are emerging as important regulators of a variety of cellular events, including cell proliferation, differentiation, and apoptosis [97–98]. With respect to SM, another important issue is that it is highly repre‐ sented in PM of RSC but during satellite cell proliferation and subsequent differentiation it is almost undetectable [85]. One has to bear in mind that RSC as being stem cells undergo either symmetric or asymmetric division and that in the identical culture conditions they adopt characteristics consistent with a return to quiescent-like state [99]. Thus, it is apparent that certain activated satellite cells (ASC) by unknown mechanism are withdrawn from the cell cycle and they escape from the differentiation program. Cell decision whether to differentiate or not to differentiate is determined by the composition of PM and LR representation in particular. Under the appropriate conditions, SC differentiate into muscle cells with phenotype characterized by the accumulation of muscle contractile proteins and increased sensitivity to insulin. In these differentiated cells, insulin accelerates myogenesis [43]. Insulin initially stimulates proliferation, and subsequently, it stops cell divisions and stimulates metabolic pathways to promote protein synthesis. A clear explanation of how these signaling pathways elaborate such radically different physiological responses in this differentiated tissue has remained elusive, although compartmentalization and switching-off signaling molecules has been proposed [43]. Insulin activates their respective tyrosine kinase receptors to phosphory‐ late key residues on a "docking protein" or the receptor, respectively, which recruits multiple adaptor proteins. Recruited proteins include the GDP exchange factor Son of Sevenless (SOS), which activates the Ras/Raf/MEK/ERK mitogen-activated protein kinase cascade (mitogenic‐ ity), or the p85 regulatory subunit of PI3-kinase, which stimulates signaling pathways

126 Muscle Cell and Tissue

Although the molecular mechanisms that regulate the differentiation of satellite cells and myoblasts toward myofibers are not fully understood, cell membrane lipids and proteins that sense and respond to their environment must play an important role. Heat alters PM physical state into more fluidic form, and similar effect may be artificially induced by membrane fluidizers [104]. Interestingly, heat-induced hyperfluidization in animal PM is associated with the activation of the cholesteryl glucoside (CG) synthetase (glucosyltransferase) located in LR, the enzyme that catalyzes the transfer of the glucose moiety from glucose donor sphingolipid glucosylceramide to cholesterol [105]. CG production alters membrane physical properties and forms thermostable solid-ordered domains. Notably, CG and other steryl glucosides act as important lipid mediators in the process of heat shock factor-1 (HSF-1) activation. This transcription factor regulates the expression of heat shock proteins (HSPs), which are critical for the survival of cells [104]. Some authors showed that the alteration of membrane fluidity by heat or membrane fluidizer treatment causes the reorganization of lipid rafts linked to activation of heat shock response mediated by HSF-1 activation and HSP induction [106–108]. It is suggested by Kunimoto et al. [110–111] that PM fluidity leads to CG formation and the latter mediates HSF-1 activation and HSP induction. There is growing body of evidence that strategies aimed at increasing levels of HSPs may be successful in protecting cells in neuro‐ degenerative diseases. At least in the animal model of amyotrophic lateral sclerosis (ALS), increasing HSP levels by treatment with arimoclomol (hydroxylamine derivative) delayed disease progression in mice [112, 113]. Another hydroxylamine derivative, namely, BGP-15 inhibited acetaminophen-induced caspase-independent apoptosis of hepatocytes [106]. The prime HSPs induced by heat stress or membrane fluidizers are HSP70 and HSP90. Importantly, HSP72 preserves muscle function and slows progression of severe muscular dystrophy [114]. Under normal circumstances, chaperone proteins involved in protein quality control can prevent protein aggregation by binding of misfolded proteins as soon as they are produced during translation or later during their organization into supramolecular structures, thereby assisting protein refolding or else in targeting for degradation [115].
