Statin administration activates system xC− in skeletal muscle: a potential mechanism explaining statin-induced muscle pain

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC−, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC− activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC− activation, as cotreatment with sulfasalazine (system xC− inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC− substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.

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PGC1α−1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals

PPAR Research ◽

10.1155/2014/895734 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Tara M. Henagan ◽

Laura K. Stewart ◽

Laura A. Forney ◽

Lauren M. Sparks ◽

Neil Johannsen ◽

...

Keyword(s):

Skeletal Muscle ◽

Splice Variant ◽

Disease Risk ◽

Transcriptional Start Site ◽

Cardiovascular Disease Risk ◽

Nucleosome Position ◽

Muscle Metabolism ◽

Lower Percentage ◽

Fat Percentage ◽

Cvd Risk

PGC1α, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism.PGC1αundergoes splicing to produce several mRNA variants, with theNTPGC1αvariant having a similar biological function to the full lengthPGC1α(FLPGC1α). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined byPGC1αexpression.PGC1αexpression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal musclePGC1α −1 nucleosome (−1N) position is associated with splice variantNTPGC1αbut notFLPGC1αexpression. Division of participants based on the −1N position revealed that those individuals with a −1N phased further upstream from the transcriptional start site (UP) expressed lower levels ofNTPGC1αthan those with the −1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the −1N may be a potential epigenetic regulator ofNTPGC1αsplice variant expression, and −1N position andNTPGC1αvariant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifierNCT00458133.

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Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism

AJP Cell Physiology ◽

10.1152/ajpcell.00540.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. C615-C626 ◽

Cited By ~ 9

Author(s):

Ahmed M. Abdelmoez ◽

Laura Sardón Puig ◽

Jonathon A. B. Smith ◽

Brendan M. Gabriel ◽

Mladen Savikj ◽

...

Keyword(s):

Experimental Data ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Glycogen Synthesis ◽

C2c12 Myotubes ◽

Mrna Levels ◽

Cellular Models ◽

L6 Myotubes ◽

Human Myotubes ◽

Human Skeletal Muscle Cells

Rat L6, mouse C2C12, and primary human skeletal muscle cells (HSMCs) are commonly used to study biological processes in skeletal muscle, and experimental data on these models are abundant. However, consistently matched experimental data are scarce, and comparisons between the different cell types and adult tissue are problematic. We hypothesized that metabolic differences between these cellular models may be reflected at the mRNA level. Publicly available data sets were used to profile mRNA levels in myotubes and skeletal muscle tissues. L6, C2C12, and HSMC myotubes were assessed for proliferation, glucose uptake, glycogen synthesis, mitochondrial activity, and substrate oxidation, as well as the response to in vitro contraction. Transcriptomic profiling revealed that mRNA of genes coding for actin and myosin was enriched in C2C12, whereas L6 myotubes had the highest levels of genes encoding glucose transporters and the five complexes of the mitochondrial electron transport chain. Consistently, insulin-stimulated glucose uptake and oxidative capacity were greatest in L6 myotubes. Insulin-induced glycogen synthesis was highest in HSMCs, but C2C12 myotubes had higher baseline glucose oxidation. All models responded to electrical pulse stimulation-induced glucose uptake and gene expression but in a slightly different manner. Our analysis reveals a great degree of heterogeneity in the transcriptomic and metabolic profiles of L6, C2C12, or primary human myotubes. Based on these distinct signatures, we provide recommendations for the appropriate use of these models depending on scientific hypotheses and biological relevance.

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Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00410.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. R1110-R1119 ◽

Cited By ~ 25

Author(s):

Phoebe A. Stapleton ◽

Adam. G. Goodwill ◽

Milinda E. James ◽

Jefferson C. Frisbee

Keyword(s):

Skeletal Muscle ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Nordihydroguaiaretic Acid ◽

Arachidonic Acid Metabolism ◽

Density Lipoprotein Receptor ◽

Oxide Synthase ◽

Cytochrome P 450

With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 wk of age, we tested the hypothesis that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P-450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/Bl/6J (C57) controls. However, although inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57 controls, this effect was absent in ApoE or LDLR strains. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, although combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57 controls, significant reactivity remained in ApoE and LDLR strains. Whereas inhibition of cytochrome P-450 ω-hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR strains, inhibition of 12/15-lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR strains demonstrated an increased production of both 12( S)- and 15( S)-hydroxyeicosatetraenoic acid, end products of arachidonic acid metabolism via 12/15-lipoxygenase, a response that was not present in C57 controls. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact.

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Cardiovascular Consequences of Skeletal Muscle Impairments in Breast Cancer

Sports ◽

10.3390/sports8060080 ◽

2020 ◽

Vol 8 (6) ◽

pp. 80

Author(s):

Gabriel H. Zieff ◽

Chad W. Wagoner ◽

Craig Paterson ◽

Patricia Pagan Lassalle ◽

Jordan T. Lee

Keyword(s):

Breast Cancer ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Cancer Survivors ◽

Aerobic Exercise ◽

Breast Cancer Survivors ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Exercise Intolerance ◽

Peak Oxygen Consumption

Breast cancer survivors suffer from disproportionate cardiovascular disease risk compared to age-matched controls. Beyond direct cardiotoxic effects due to treatments such as chemotherapy and radiation, breast-cancer-related reductions in skeletal muscle mass, quality and oxidative capacity may further contribute to cardiovascular disease risk in this population by limiting the ability to engage in aerobic exercise—a known promoter of cardiovascular health. Indeed, 20–30% decreases in peak oxygen consumption are commonly observed in breast cancer survivors, which are indicative of exercise intolerance. Thus, breast-cancer-related skeletal muscle damage may reduce exercise-based opportunities for cardiovascular disease risk reduction. Resistance training is a potential strategy to improve skeletal muscle health in this population, which in turn may enhance the capacity to engage in aerobic exercise and reduce cardiovascular disease risk.

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