Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mevalonic Acid”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed1986

The role of circulating mevalonate in nephrotic hypercholesterolemia in the rat.

The cause of the hypercholesterolemia that characterizes the nephrotic syndrome has never been adequately explained. The present study examines the possibility that enhanced availability of the cholesterol precursor, mevalonic acid, to the liver in the nephrotic state may result in increased hepatic cholesterogenesis. In normal animals, the kidneys are known to be the major site of the metabolism of circulating mevalonate to both cholesterol and CO2. Previous studies, using perfusion of isolated, intact kidneys, have shown that the excretion and metabolism of mevalonate are both impaired in nephrosis. The present investigation has demonstrated in vivo that puromycin aminonucleoside nephrosis results in a 25% reduction in the oxidation of mevalonate to CO2. In the same nephrotic animals, cholesterogenesis from circulating mevalonate was significantly increased in both liver and carcass. In addition, liver slices from nephrotic animals incorporated increased amounts of [5-14C]mevalonate into cholesterol when calculated per whole liver, but not per gram of liver. Oxidation of mevalonic acid by kidney slices was significantly reduced, whether expressed as per gram of tissue or per whole organ. HMG-CoA (3-hydroxy-3-methylglutaryl) reductase activity in liver of nephrotic animals was significantly increased. We conclude that, in the nephrotic state, impaired mevalonate metabolism by the kidney may contribute to enhanced cholesterogenesis by increasing delivery of mevalonate to liver and carcass; in addition, nephrosis appears to provide an undefined stimulus for HMG-CoA reductase activity in the liver, thereby providing an additional enhancement of hepatic cholesterogenesis.

Animals↗
PubMed1970

The synthesis of bile acids in perfused rat liver subjected to chronic biliary drainage.

1. Isolated rat liver was perfused with heparinized whole blood under physiological pressure resulting in the secretion of bile at about the rate observed in vivo. 2. The preparation remained metabolically active for 4h and was apparently normal in function and microscopic appearance. 3. When the perfusate plasma and liver cholesterol pool was labelled by the introduction of [2-(14)C]mevalonic acid the specific radioactivity of the perfusate cholesterol increased. The biliary acids (cholic acid and chenodeoxycholic acid) were labelled and had the same specific radioactivity. 4. Livers removed from rats immediately after, and 40h after, the start of total biliary drainage, were perfused; increased excretion rates of both cholic acid and chenodeoxycholic acid were found when the liver donors had been subjected to biliary drainage. 5. The incorporation of [2-(14)C]mevalonic acid or rat lipoprotein labelled with [(14)C]cholesterol into bile acids was studied. 6. A dissociation between the mass of bile acid excreted and the rate of incorporation of (14)C was found. This was attributed to the changing specific radioactivity of the cholesterol pool acting as the immediate bile acid precursor.

Animals↗
PubMed1990

Differential regulation of hepatic triglyceride lipase and 3-hydroxy-3-methylglutaryl-CoA reductase gene expression in a human hepatoma cell line, HepG2.

The level of hepatic triglyceride lipase (H-TGL) synthesis and secretion was examined in response to changes in cholesterol biosynthesis in the human hepatoma cell line HepG2. Cells were first fed a lipoprotein-deficient serum-supplemented medium to eliminate exogenous cholesterol. Mevinolin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, was then added at a concentration (37 microM) which inhibited cholesterol biosynthesis by greater than 85% and decreased total cell cholesterol from 36.1 to 27.4 micrograms/ml of cell protein. Mevinolin treatment caused a 4.9 +/- 0.8-fold increase in the amount of H-TGL activity secreted into the medium, a 1.8 +/- 0.4-fold rise in H-TGL-specific mRNA, and a concurrent 14-fold increase in HMG-CoA reductase mRNA. Addition of 1 mM mevalonic acid to normal or mevinolin-treated cells raised the cellular cholesterol content and decreased the amount of secreted H-TGL activity to levels below control values. Mevalonic acid also prevented mevinolin-induction of H-TGL and HMG-CoA reductase mRNA, suggesting a common regulatory step for H-TGL and HMG-CoA reductase. Exposure of cells to mevinolin and 25-hydroxycholesterol together resulted in a marked repression of HMG-CoA reductase mRNA levels, whereas these conditions further enhanced the secretion of H-TGL activity and the expression of H-TGL mRNA. These results demonstrate a differential role for 25-hydroxycholesterol in the regulation of H-TGL and HMG-CoA reductase expression.

Carcinoma, Hepatocellular↗
PubMed1979

Isolation of 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-3 beta-ol from ester fractions of nutritionally deprived Neurospora crassa.

A method of isolating pure fractions of 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-38-ol for sterol intermediate studies is described. Starvation cultures of Neurospora crassa readily incorporate exogenous mevalonic acid into the sterol ester fraction. Isolation involves a simple solvent extraction and two chromatograms. Only the ester fraction yielded the required purity. Radioactive 4 alpha-methyl-5 alpha-ergosta-8,24(28)-dien-3 beta-ol is readily produced from DL-[2-14C] mevalonic acid.

Cholestadienols↗
PubMed2005

Effect of statins on the proteasomal activity in mammalian endothelial and vascular smooth muscle cells.

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, effectively prevent cardiovascular events. In addition to their lipid lowering properties, a variety of pleiotropic effects on cardiovascular cells were demonstrated in vitro and in vivo. It has been hypothized that statins deploy a part of their effects by targeting the proteasome. Statin-induced effects remarkably overlap with effects obtained by inhibition of the proteasome in endothelial and vascular smooth muscle cells (e.g., endothelial nitric oxide synthase (eNOS)-upregulation, attenuation of nuclear factor kappa B (NF-kappaB) activation, inhibition of proliferation). We therefore examined, whether statins modulate the proteasomal activity of vascular cells. We studied the effect of simvastatin, atorvastatin, and pravastatin as well as of the proteasome inhibitor clasto-lactacystin on morphology, proliferation, viability, and proteasomal activity in two mammalian endothelial cell lines (CPAE and Ea.hy962), and in primary vascular smooth muscle cells (VSMCs). Both statins and lactacystin induced comparable morphological changes and attenuated proliferation of calf pulmonary artery cell line (CPAE). Whereas the statin-induced effects were reversed by mevalonic acid, however, the lactacystin-induced alterations were not influenced by mevalonic acid. As expected, lactacystin caused a significant loss of proteasomal activity measured in the extract of treated CPAE cells, whereas the extracts of statin-treated CPAEs exhibited unchanged activities. This result was also confirmed in Ea.hy926 cells and in primary rat VSMCs. We show here, that even high doses of statins do not modulate the activities of purified human 20S proteasomes. We conclude that the similar biological effects of statins and proteasome inhibitors in vascular cells are not due to a common inhibitory mechanism of action on the proteasome.

Animals↗
PubMed1997

Prenylation of proteins in Trypanosoma brucei.

Prenyl modification of proteins by farnesyl and geranylgeranyl isoprenoids occurs in a variety of eukaryotic cells. Culturing of Trypanosoma brucei in the presence of [3H]mevalonolactone (which is hydrolyzed in cells to give mevalonic acid, the precursor of protein prenyl groups) and an inhibitor of mevalonic acid biosynthesis leads to the radiolabeling of a specific set of proteins when analyzed by gel electrophoresis. T. brucei proteins were also labeled when cells were cultured in the presence of [3H]farnesol or [3H]geranylgeraniol, and each prenol labels a distinct set of proteins. Unlike mammalian cells, only a few T. brucei proteins of molecular weights similar to those of the mammalian Ras superfamily of GTPase (20-30 kDa) were labeled with [3H]farnesol or [3H]geranylgeraniol. When the 0-55% ammonium sulfate fraction of T. brucei cytosol was fractionated on anion exchange chromatography, protein farnesyltransferase (PFT) and protein geranylgeranyltransferase-I (PGGT-I) activities were detected and elute as two distinct peaks. Partially purified T. brucei PFT and PGGT-I display partly different specificities toward prenyl acceptor substrates from those of mammalian protein prenyltransferases. As shown previously, rat PFT utilizes proteins ending in CVLS and CVIM as efficient prenyl acceptors and rat PGGT-I utilizes proteins ending in CVLL and CVIM in vitro. On the contrary, T. brucei PFT farnesylates a protein ending in CVIM but not CVLS or CVLL, and T. brucei PGGT-I preferentially geranylgeranylates a protein ending in CVLL.

Alkyl and Aryl Transferases↗
PubMed1990

Lovastatin decreases coenzyme Q levels in rats.

Lovastatin is used for the treatment of hypercholesterolemia. It functions by inhibiting the enzyme, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34), that is required for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonic acid. Since biosynthesis of both cholesterol and coenzyme Q (CoQ) requires mevalonic acid as a precursor, it was considered that lovastatin therapy would also result in a lowering of cellular CoQ levels. This study was conducted to determine whether lovastatin treatment does decrease CoQ levels and whether such decreases can be prevented by CoQ supplementation. Forty-five adult male Holtzman rats were randomly assigned to one of three treatment groups. Controls were fed ground laboratory rat chow ad libitum. The other two groups were fed ground laboratory rat chow containing 400 mg of lovastatin per kg of diet ad libitum. One of the lovastatin-fed groups received CoQ10 (15 mg per kg of body weight) daily via stomach intubation. After 4 weeks, samples of heart, liver, and blood were analyzed for CoQ concentrations. Results indicated that CoQ concentrations in all tissues analyzed were decreased in lovastatin-treated rats. Lovastatin-treated animals that were supplemented with CoQ10 had blood, heart, and liver CoQ10 concentrations that approximated or exceeded those of control animals. It is concluded that lovastatin does indeed lower tissue concentrations of CoQ and that a return to normal can be achieved by supplementation with CoQ.

Animals↗
PubMed1980

Retention of the 4-pro-R hydrogen atom of mevalonate at C-2,2' of bacterioruberin in Halobacterium halobium.

Intact cells of Halobacterium halobium fed with (3R,4R)-[2-14C,4-3H1]mevalonic acid were found to incorporate label into acyclic C40 and C50 carotenoids, of which bacterioruberin was the most abundant. The 14C/3H ratios of the isolated carotenoids demonstrated that the 4-pro-R hydrogen atom of mevalonic acid was retained at the C-2 and C-2' positions of bacterioruberin. Diphenylamine was found to inhibit the production of bacterioruberin.

Carbon Radioisotopes↗
PubMed1996

Biosynthesis of [14C]geranylgeranyldiphosphate by a prenyl transferase system from a mutant strain of Gibberella fujikuroi.

[14C]Geranylgeranyldiphosphate was produced by a prenyl transferase system extracted from the mutant strain SG4 of Gibberella fujikuroi (wild-type strain IMI 58289), which is blocked in carotenoid biosynthesis. The fungus was grown in liquid medium containing only potato-dextrose broth. Crude extracts of 12- to 14-day-old mycelia in Tris buffer, pH 8.5, were centrifuged at 100,000g. The supernatant was desalted and used to produce [4,8,12,16-14C]geranylgeranyldiphosphate from R,S-[2-14C]mevalonic acid. Maximum yield of [14C]geranylgeranyldiphosphate was obtained using mycelia from the stationary growth phase with incubation of the enzyme preparation at pH 8.5 for 5 h. Routinely, 65% of the biogenetic available R-mevalonic acid was converted to [14C]geranylgeranyldiphosphate, which was identified by cochromatography with authentic [1-3H]geranylgeranyldiphosphate by means of radio-TLC, radio-HPLC, and hydrolysis to geranylgeraniol.

Chromatography, High Pressure Liquid↗
PubMed1974

Production of plasma esterified cholesterol in lean, normotriglyceridemic humans.

The rate of production of plasma esterified cholesterol was measured both in vivo and in vitro in seven subjects and in vivo alone in eight subjects. All subjects were lean, clinically healthy, and had triglyceride concentrations less than 1.5 micro moles/ml. In vivo production was calculated from the labeling of free and esterified cholesterol in plasma samples collected at 1-hr intervals for 8 hr after an intravenous injection of [(3)H]mevalonic acid, on the assumption that plasma free cholesterol was the sole immediate precursor of esterified cholesterol. In vitro production was measured in serum samples collected 1 hr after the injection of [(3)H]mevalonic acid (when radioactivity in esterified cholesterol was very low relative to that in free cholesterol); these samples were incubated for 1 hr at 37 degrees C. The rates measured in vivo and in vitro were very similar in the seven subjects, strengthening the confidence in the techniques. In vivo production was measured during the postabsorptive state in all 15 subjects and in 5 of them also during the last 8 hr of a 32-56-hr period when all calories were taken in three hourly meals of an 80% carbohydrate, fat-free formula. In the postabsorptive state there was no apparent relationship between the production of esterified cholesterol and the concentration of either free or esterified cholesterol. Rather, despite a wide range of cholesterol concentrations, esterified cholesterol production was similar in all subjects. During the carbohydrate consumption the esterified cholesterol concentrations were significantly lower than during the postabsorptive state, but there was virtually no change in rate of production. It has been concluded that the differences in concentration of esterified cholesterol in lean, normotriglyceridemic subjects cannot be explained solely on the basis of differences in its production.

Adult↗
PubMed1997

Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin.

HMG-CoA reductase inhibitors or statins are effective in both the primary and secondary prevention of coronary heart disease, the extent of benefit being proportional to the reduction in low density lipoprotein (LDL) cholesterol achieved. Atorvastatin, a newly licensed compound, reportedly lowers LDL with greater efficacy than other statins. The mechanism of this action was, therefore, explored in twenty patients with refractory familial hypercholesterolemia who received in a single-blind sequence simvastatin 40 mg/day, placebo and atorvastatin 10 mg/day each for 4 weeks. At the end of the placebo period the effects of single 40-mg doses of simvastatin and atorvastatin on plasma levels and urinary excretion of mevalonic acid, indices of HMG-CoA reductase activity, were compared. Administration of atorvastatin 10 mg daily for 1 month lowered LDL cholesterol by 32.5%, compared with placebo (P = 0.0001), which was 4.5% less than the decrease after simvastatin 40 mg daily (P = 0.33). The area under the plasma curve and urinary mevalonic acid/ creatinine ratio were both significantly less during the 24 h after a single dose of atorvastatin 40 mg than after a single dose of simvastatin 40 mg (P < 0.01). These findings suggest that the greater efficacy of atorvastatin compared with simvastatin is due to more prolonged inhibition of HMG-CoA reductase, presumably reflecting longer residence of atorvastatin or its active metabolites in the liver.

Anticholesteremic Agents↗
PubMed2006

Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma.

BACKGROUND: Statins have anti-inflammatory effects on immune cells. OBJECTIVE: To investigate the immunomodulatory effects of fluvastatin on peripheral blood mononuclear cells (PBMCs) after allergen-specific and non-allergen-specific stimulation in patients with asthma and in healthy subjects. METHODS: PBMCs from seven patients with asthma who showed elevated immunoglobulin (Ig)E to house dust mite were isolated and stimulated with Dermatofagoides farinae, purified protein derivative, and phytohaemagglutinin (PHA) in the presence or absence of fluvastatin. PBMCs from seven healthy subjects were stimulated with PHA. The effects of fluvastatin on cell proliferation and production of cytokines (interferon [IFN]-gamma and interleukin [IL]-5) and chemokines (chemokine CXC motif, ligand [CXCL10], and CC chemokine ligand [CCL17]) were measured. Migration of T helper (Th)1 and Th2 cell lines was also investigated. The expression of CXCR3 and CCR4 was analysed with flow cytometry. Steroid-insensitive PBMCs induced by preculture with IL-2 and IL-4 were also evaluated. Some experiments were performed in the presence of mevalonic acid. RESULTS: Fluvastatin inhibited the proliferation of PBMCs and decreased the production of IL-5, IFN-gamma, CCL17, and CXCL10 after allergen-specific and non-allergen-specific stimulation; all these effects, except for decreased CXCL10 production, were partially reversed by mevalonic acid. Culture supernatants obtained in the presence of fluvastatin prevented the migration of Th1 and Th2 cell lines in a dose-dependent manner. In addition, CCR4 and CXCR3 expression on CD4(+) T cells was not affected by the presence of fluvastatin. Fluvastatin inhibited the proliferative response of steroid-insensitive PBMCs to phytohaemagglutinin. CONCLUSION: Fluvastatin has inhibitory effects on cytokine and chemokine production, and thus might be used as a potential therapeutic agent in severe asthma.

Adult↗
PubMed1991

Isoprenylation of rap2 proteins in platelets and human erythroleukemia cells.

The covalent modification of proteins by isoprenoid derivatives of mevalonic acid was investigated in human platelets, cells that lack the ability to synthesize endogenous cholesterol, and human erythroleukemia (HEL) cells, cholesterol-producing cultured cells derived from megakaryocytes. When washed platelets or HEL cells were incubated with [3H]mevalonic acid, the radiolabel was incorporated into a distinct group of proteins with molecular masses between 21,000 and 28,000. We have identified one of these proteins as a ras-related rap2 protein based on its immunoreactivity with a polyclonal antiserum raised against purified recombinant rap2b. This anti-rap2 antiserum was used for two-dimensional immunoblotting analysis and immunoprecipitation of mevalonate-labeled rap2 from platelets and HEL cells. These results suggest that rap2 may undergo a series of carboxyl-terminal modifications similar to the p21ras proteins. In addition, it is shown that non-cholesterol-producing cells are capable of incorporating isoprenyl groups into specific proteins.

Blood Platelets↗
PubMed2003

Cloning, expression, and purification of His-tagged rat mevalonate kinase.

Mevalonate kinase catalyzes the phosphorylation of mevalonic acid to form mevalonate 5-phosphate, which plays a key role in regulating cholesterol biosynthesis in animal cells. Deficiency of mevalonate kinase activity in the human body has been linked to mevalonic aciduria and hyperimmunoglobulinemia D/periodic fever syndrome (HIDS). We cloned the gene of rat mevalonate kinase into a bacterial expression vector pLM1 with six continuous histidine codons attached to the 5(') of the gene. The cloned gene was overexpressed in Escherichia coli and the soluble protein was purified with a nickel HiTrap chelating metal affinity column in 90% yield to apparent homogeneity. The purified rat mevalonate kinase had a dimeric structure composed of identical subunits. Based on SDS-PAGE, the subunit was 42 kDa. The specific activity of the purified His-tagged rat mevalonate kinase was 32.7 micromol/min/mg and the optimal pH was found to be 7.0-8.0 in phosphate buffer. The Michaelis constant K(M) was 35 microM for (RS)-mevalonate and 953 microM for ATP, respectively. The V(max) was determined to be 38.7 micromol/min/mg. The overexpression of rat mevalonate kinase in E. coli and one-step purification of the highly active rat mevalonate kinase will facilitate further our investigation of this enzyme through site-directed mutagenesis and enzyme-catalyzed reactions with substrate analogs.

Animals↗
PubMed1970

Biosynthesis of cholesterol in rabbit reticulocytes and its exchange with plasma.

When rabbit reticulocytes were incubated in normal blood plasma containing mevalonic acid-2-(14)C, radioactivity was incorporated into cholesterol, cholesteryl esters, and squalene in the cells. The squalene reached a steady level of radioactivity much more rapidly than did cholesterol. Rabbit reticulocytes which were labeled as a result of previous incubation with mevalonic acid-2-(14)C were incubated with normal autologous blood plasma. The specific activity of the cholesterol in the plasma rapidly became higher than that of the cells. This suggests that there is compartmentation of cholesterol in the reticulocyte and that a pool involved in exchange with plasma cholesterol has a specific activity which is much higher than the average for the whole cell.

Animals↗
PubMed2006

Biosynthesis of mono- and sesquiterpenes in strawberry fruits and foliage: 2H labeling studies.

The biosynthesis of the monoterpene (S)-linalool and the sesquiterpene trans-(S)-nerolidol in fruits of Fragaria x ananassa Duch. cv. Eros and Florence and of the monoterpene (-)-alpha-pinene in Fragaria vesca was investigated by in vivo feeding experiments with [5,5-2H2]mevalonic acid lactone (d2-MVL) and [5,5-2H2]-1-deoxy-d-xylulose (d2-DOX). The feeding experiments indicate that (S)-linalool and trans-(S)-nerolidol in Fragaria x ananassa Duch. and (-)-alpha-pinene in F. vesca are exclusively synthesized via the cytosolic mevalonic acid pathway without any contribution from the plastidial 1-deoxy-D-xylulose/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) route. Inhibition experiments revealed that even the presence of mevastatin, an export of plastid-derived isopentyl diphosphate/dimethylallyl diphosphate, cannot be induced. However, the enantioselective analysis shows that in Fragaria x ananassa Duch. cv. Eros and Florence both linalool enantiomers are present and that only (S)-linalool is labeled after administration of d2-MVL. Therefore, the origin of (R)-linalool in these fruits remains unknown. Contrarily, in Fragaria x ananassa Duch. foliage (R)-linalool is the dominant enantiomer. Feeding experiments revealed an incorporation of d2-MVL and d2-DOX at equal rates exclusively into (S)-linalool. Only in F. vesca foliage, where (R)-linalool is present at high enantiomeric purity (ee > 90%), is a de novo biosynthesis of the (R)-enantiomer via the DOXP/MEP pathway detectable. These results demonstrate a complex intraplant variation of (R)- and (S)-linalool biosynthesis via the cytosolic and plastidial route.

Acyclic Monoterpenes↗
PubMed2005

Induction of de novo volatile terpene biosynthesis via cytosolic and plastidial pathways by methyl jasmonate in foliage of Vitis vinifera L.

The terpene biosynthesis in leaves of Vitis vinifera L. cv. Morio Muskat was studied using methyl jasmonate to induce defensive responses in vivo. The experiments demonstrated the strong activation of the de novo biosynthesis of terpenoids via the octadecanoid-signaling cascade and release of the compounds to the gas phase. Feeding experiments with [5,5-(2)H(2)]-1-deoxy-d-xylulose and [5,5-(2)H(2)]mevalonic acid lactone allowed the investigation of the dynamic allocation of resources via the mevalonic acid and 1-deoxy-d-xylulose/2-C-methyl-d-erythritol 4-phosphate (DOXP/MEP) pathway under induced conditions and after treatment with the specific inhibitors mevastatin and fosmidomycin. The experiments reveal that monoterpenes are almost exclusively synthesized via the DOXP/MEP pathway, whereas sesquiterpenes are generated via both pathways at approximately equal rates. The biosynthesis of the homoterpene (E)-4,8-dimethyl-1,3,7-nonatriene was not affected by mevastatine or fosmidomycin.

Acetates↗
PubMed2005

Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells.

The 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are widely used and well tolerated cholesterol-lowering drugs. In rare cases, side effects occur in skeletal muscle, including myositis or even rhabdomyolysis. However, the molecular mechanisms are not well understood that lead to these muscle-specific side effects. Here, we show that statins cause apoptosis in differentiated human skeletal muscle cells. The prototypical representative of statins, simvastatin, triggered sustained intracellular Ca(2+) transients, leading to calpain activation. Intracellular chelation of Ca(2+) completely abrogated cell death. Moreover, ryanodine also completely prevented the simvastatin-induced calpain activation. Nevertheless, an activation of the ryanodine receptor by simvastatin could not be observed. Downstream of the calpain activation simvastatin led to a translocation of Bax to mitochondria in a caspase 8-independent manner. Consecutive activation of caspase 9 and 3 execute apoptotic cell death that was in part reversed by the coadministration of mevalonic acid. Conversely, the simvastatin-induced activation of calpain was not prevented by mevalonic acid. These data delineate the signaling cascade that leads to muscle injury caused by statins. Our observations also have implications for improving the safety of this important medication and explain to some extent why physical exercise aggravates skeletal muscle side effects.

Apoptosis↗