**7. Isoprenoids limit skeletal muscle regeneration**

lysophosphatidic acid (LPA) acting on GPCRs which in turn activate a Gα<sup>i</sup> protein. Besides,

Uncommon myopathic changes resultant from statin therapy offer the opportunity to gain new insight for the function of biochemical pathways downstream to HMG-CoA reductase in skeletal muscles. Irrespective of the type of statin treatment (hydrophilic or hydrophobic), the viability of skeletal muscle cells is considerably reduced, though the effect depends largely on the pharmacokinetic and pharmacodynamic properties of statins [56–57], while the signaling pathway(s) and molecular mechanisms are still not fully understood. Sometimes, signal transduction is dependent on small GTPase proteins that cycle between an inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound state. The posttranslational prenylation of these proteins occurs by the covalent addition of only two types of isoprenoids, FPP and GGPP, to cysteine residues at or near the C-terminus. Upon tyrosine kinase receptor activation, the prenylated (PM protoplasmic/inner leaflet attached) small GTPase protein Ras (MAPK kinase kinase kinase) binds GTP and becomes activated to initiate MAPK cascade ending with the stimulation of muscle cell growth (hyperplasia). In addition, small GTPase protein Rab1 (more than 60 Rab small GTPase isoforms have been identified) is involved in organelle biogenesis and intracellular vesicular trafficking [58]. Overall growth and survival signals depend on the activation of both protein receptor and

Several lines of evidence suggest particular significance of IGF-1/PI3-K/AKT cascade in maintaining muscle cell growth and viability [59–61] likely through the suppression of FOXOdependent activity of atrogin/MAFbx ubiquitin ligase gene required for the development of muscle atrophy [62–63]. Moreover, the statin-induced muscle damage is controlled by PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of statin-induced muscle atrophy [64]. In *in vivo* model, simvastatin downregulated PI3-K/AKT signaling and upregulated FOXO transcription factors and downstream gene targets known to be implicated in muscle cachexia [63]. Insulin and IGF-1 are widely known agonists of their cognate receptors (IR and IGF-1R, respectively), although at concentrations higher than physiological cross-reactivity of insulin to IGF-1R and IGF-1 to IR were observed. On the other hand, LR have been shown to be platforms to initiate cellular signal transduction of IGF-1 and insulin-inducing skeletal muscle differentiation and hyper‐ trophy. Notably, the impaired insulin/IGF-1 signaling [65–67] mimics the side effects of statin administration, whereas insulin and/or IGF-1 were reported to overcome statin-induced myopathy [61]. IR and IGF-1R with their intrinsic tyrosine kinase activities transduce the signal by recruiting insulin receptor substrate-1 (IRS-1) with its src-homology 2 domains (SH2) to the receptor phosphotyrosines. IRS-1 activates PI3-K/AKT/mTOR and Ras/Raf/MEK/ERK path‐ ways, however, phosphoinositide 3-kinase (PI3-K) as a lipid kinase converts plasma mem‐ brane phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). The latter attracts kinases with pleckstrin homology domain (PH) downstream to PI3- K including phosphoinositide-dependent kinase 1 and 2 (PDK1, PDK2) and AKT. Depletion

in signal propagation with resulting localization of Gα and Gβγ proteins.

 enhanced muscle regeneration and caused switch to oxidative fibers and can act as a counterbalance to MuRF1 and MAFbx/atrogin-1. To sum up, lipid structures play active role

Gα<sup>i</sup>

122 Muscle Cell and Tissue

nonreceptor tyrosine kinases.

While human and animal studies have demonstrated that statin treatment may reduce serum CoQ10 levels [2, 69], ubiquinone levels in human skeletal muscle do not appear to be affected by statins [61, 70]. Possible significance of some reactions and intermediates in CHOL synthesis indicate that GGPP and FPP as isoprene units play very important role in muscle cell survival and regeneration. The posttranslational prenylation of proteins such as heterotrimeric G proteins, small G-proteins, and lamins enables these proteins to anchor to cell membranes, whereas N-linked glycosylation of insulin and IGF-1 membrane receptors mediated by dolichols establishes their proper biological functions (sensitivity to ligands). Dolichols serve as carriers and situate the core oligosaccharide to be assembled to protein molecules. From some studies, it appears that it is mevalonate and isoprene units (GGPP and FPP) as their downstream intermediates rather than CHOL play the key role in statin-induced myotoxicity. Consequently, replacement of depleted mevalonate reversed the changes induced by statins, where squalene synthase or squalene epoxidase (steps in CHOL synthesis) inhibitors at concentrations sufficient to inhibit entirely CHOL synthesis did not affect muscle cell viability [71–72]. These observations point to cardinal role played by isoprenoids in physiology of skeletal muscle cells. Interestingly, statins which are sometimes harm to skeletal muscle cells do not act adversely on myocardium, a type of striated musculature. Substantial difference in the sensitivity of skeletal muscle cells and cardiomyocytes to the statin-induced myopathy could be related to dissimilar mechanisms that control viability of these cells [73]. Alterna‐ tively, it was postulated that Ca2+ homeostasis alterations could account for statin-induced muscular side effects [74, 75].
