The prevalence of exercise prescription-related course offerings in United States pharmacy school curricula: Exercise is Medicine.

Exercise training has proven to be beneficial in the prevention of disease. In addition, exercise can improve the pathogenesis and symptoms associated with a variety of chronic disease states and can attenuate drug-induced adverse effects. Exercise is a drug-free polypill. Because the benefits of exercise are clear and profound, Exercise is Medicine, a joint initiative between the American Medical Association and American College of Sports Medicine, was launched in 2007 to call on all health care providers to counsel patients and prescribe exercise in the prevention and treatment of chronic disease states. Pharmacists play an increasing role in direct patient care and are the most accessible health care providers in the community. Thus, pharmacists should be knowledgeable in counseling patients on the frequency, intensity, time, and type of exercise that is appropriate for various conditions and disease states. The aim of the present study was to determine the prevalence of didactic course offerings in United States pharmacy school curricula regarding training in exercise prescription. School websites were accessed for information regarding course offerings in PharmD programs. No United States pharmacy schools offered courses that were dedicted to the role of exercise in disease prevention or exercise prescription in disease management. Ninety percent of pharmacy schools did not offer courses with the keywords "exercise," "fitness, or "physical activity" in the title or description. The data suggest that student pharmacists are not adequately trained to counsel patients on the benefits of exercise or exercise prescription.

Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Doxorubicin (Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.

Effects of acute doxorubicin treatment on hepatic proteome lysine acetylation status and the apoptotic environment.

AIM: To determine if doxorubicin (Dox) alters hepatic proteome acetylation status and if acetylation status was associated with an apoptotic environment. METHODS: Doxorubicin (20 mg/kg; Sigma, Saint Louis, MO; n = 8) or NaCl (0.9%; n = 7) was administered as an intraperitoneal injection to male F344 rats, 6-wk of age. Once animals were treated with Dox or saline, all animals were fasted until sacrifice 24 h later. RESULTS: Dox treatment decreased proteome lysine acetylation likely due to a decrease in histone acetyltransferase activity. Proteome deacetylation may likely not be associated with a proapoptotic environment. Dox did not increase caspase-9, -8, or -3 activation nor poly (adenosine diphosphate-ribose) polymerase-1 cleavage. Dox did stimulate caspase-12 activation, however, it likely did not play a role in apoptosis induction. CONCLUSION: Early effects of Dox involve hepatic proteome lysine deacetylation and caspase-12 activation under these experimental conditions.

Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals.

Doxorubicin (Dox) is an effective chemotherapeutic agent, but known to cause cardiac and hepatic toxicity. Mechanisms of toxicity have not been clearly identified, but shown to involve oxidative stress and mitochondrial dysfunction. However, antioxidant supplementation has only shown modest protection from Dox-induced toxicity in clinical trials. Therefore, further research is required to discern alternative mechanisms that may also play an important role in Dox-induced toxicity. Thus, we aimed to investigate the role of mitochondrial fusion and fission in Dox-induced hepatic toxicity, which has not yet been investigated. Six-week-old male F344 rats were injected IP with 20 mg/kg of Dox or saline. Once administered, both groups of animals were fasted with no food or water until sacrifice 24 h later. Dox decreased content of primary regulators of mitochondrial fusion (OPA1, MFN1, and MFN2) with no effect on regulators of fission (DRP1 and FIS1), thus shifting the balance favoring mitochondrial fission. Moreover, it was determined that mitochondrial fission was likely not coupled to cell proliferation or cytochrome c release leading to the activation of mitochondrial-mediated apoptotic signaling. Rather, mitochondrial fission may be coupled to mitophagy and may be an adaptive response to protect against Dox-induced hepatic toxicity. This is the first study to report the role of altered mitochondrial dynamics and mitophagy machinery in Dox-induced hepatic injury.

The effects of acute doxorubicin treatment on proteome lysine acetylation status and apical caspases in skeletal muscle of fasted animals.

BACKGROUND: Doxorubicin treatment is known to cause muscular weakness. However, the cellular mechanisms have not been elucidated. We aimed to determine the effects of acute doxorubicin treatment on proteome lysine acetylation status, an indication of the apoptotic and inflammatory environment, and the expression and activation of various apical caspases involved in the initiation of apoptosis. METHODS: Six-week-old male F344 rats were injected intraperitoneally with 20 mg/kg of doxorubicin or saline. Once the treatment was administered, both groups of animals were fasted with no food or water until sacrifice 24 h posttreatment. RESULTS: Doxorubicin treatment affected neither the proteome lysine acetylation status nor the expression of sirtuin 1, sirtuin 3, SOD1, or SOD2 in soleus of fasted animals. Doxorubicin treatment also did not affect the expression or activation of procaspase-1, procaspase-8, procaspase-9, or procaspase-12. CONCLUSION: We suggest that doxorubicin does not exert a direct effect on these catabolic parameters in skeletal muscle in vivo.

The role of autophagy in doxorubicin-induced cardiotoxicity.

Doxorubicin (Dox) is an effective chemotherapeutic agent, however, its use is limited by cardiotoxicity. The mechanisms causing cardiotoxicity have not been clearly elucidated, but known to involve, at least in part, oxidative stress, mitochondrial dysfunction and apoptosis. More recently, it has been suggested that dysregulation of autophagy may also play an important role in Dox-induced cardiotoxicity. Autophagy has dual functions. Under physiological conditions, autophagy is essential for optimal cellular function and survival by ridding the cell of damaged or unwanted proteins and organelles. Under pathological conditions, autophagy may be stimulated in order to protect the cell from stress stimuli or, alternatively, to contribute to cell death. Thus, appropriate regulation of autophagy can be a matter of life or death. The role of autophagy in Dox-induced cardiotoxicity has recently been explored, however, conflicting reports on the effects of Dox on autophagy and its role in cardiotoxicity exist. Most, but not all, of the studies conclude that Dox upregulates cardiac autophagy and contributes to the pathogenesis of Dox-induced toxicity. Dox may induce autophagy by suppressing the expression of GATA4 and/or S6K1, which may directly or indirectly regulate expression of essential autophagy genes such as Atg12, Atg5, Beclin1 and Bcl-2. Interestingly, the Dox-induced autophagic response may be species specific as Dox treatment has been shown to stimulate autophagy in rat models, but suppress autophagy in mouse models. Additional studies will elucidate this possibility.

Cellular and molecular mechanisms of apoptosis in age-related muscle atrophy.

Age-related muscle atrophy is due to loss of muscle fibers as well as atrophy of the remaining fibers. Evidence shows that loss of myofibers may be, in part, due to apoptosis. Two major apoptotic pathways have been extensively studied which are the mitochondrion-mediated and receptor-mediated pathways. However, other pathways exist, such as the p53 pathway. To date, it is not completely clear what pathways are responsible for loss of fibers in age-related muscle atrophy. Evidence suggests that multiple pathways may play a role. In this review article the effects of aging on the mitochondrion-, receptor-, and p53-mediated apoptotic pathways in skeletal muscle are discussed.

Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy.

Glucocorticoid-induced myopathy is a common side effect of chronic glucocorticoid therapy. Several mechanisms are currently being examined as ways in which glucocorticoid-induced myopathy occurs. These include apoptotic signaling through mitochondrial-mediated and Fas-mediated apoptosis, the role of the proteosome, the suppression of the IGF-1 signaling, and the role of ceramide in glucocorticoid-induced apoptosis and myopathy. It is difficult to differentiate which mechanism may be the initiating event responsible for the induction of apoptosis; however, all of the mechanisms play a vital role in glucocorticoid-induced myopathy.

Cellular effects of resveratrol in skeletal muscle.

Resveratrol is a stilbene found naturally in various plants with the highest concentration in the skin of grapes and peanuts. The function of this compound in plants is to confer resistance against bacterial and fungal infection. The effects of resveratrol in animals and humans are currently an area of intense investigation. Resveratrol has been shown to have a plethora of health benefits including protection against cardiovascular disease, various cancers, type II diabetes, and also has life extending properties. The beneficial effects of resveratrol in skeletal muscle have been given less attention in the literature compared to other tissues. Therefore, the focus of this review is to highlight the cellular effects of resveratrol in skeletal muscle. Resveratrol has been shown to alter protein catabolism and muscle function, and confer resistance against oxidative stress, injury, and cell death of skeletal muscle cells. The mechanisms underlying these resveratrol-induced adaptations in skeletal muscle are discussed.

Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy.

Zidovudine (3-azido-3'-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase gamma. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.