Amie J. Dirks-Naylor

The effects of vitamin D on skeletal muscle function and cellular signaling

It is thought that every cell in the body expresses the vitamin D receptor, and therefore vitamin D may play a role in health and homeostasis of every organ system, including skeletal muscle. Human, animal, and cell culture studies have collectively shown that vitamin D affects muscle strength and function. Vitamin D functions in a plethora of cellular processes in skeletal muscle including calcium homeostasis, cell proliferation, cell differentiation, fiber size, prevention of fatty degeneration, protection against insulin resistance and arachidonic acid mobilization. These processes appear to be mediated by several signaling pathways affected by vitamin D. This review aims to explore the effects of vitamin D on skeletal muscle in each model system and to delineate potential cell signaling pathways affected by vitamin D.

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.

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.

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.

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.

The benefits of coffee on skeletal muscle

Coffee is consumed worldwide with greater than a billion cups of coffee ingested every day. Epidemiological studies have revealed an association of coffee consumption with reduced incidence of a variety of chronic diseases as well as all-cause mortality. Current research has primarily focused on the effects of coffee or its components on various organ systems such as the cardiovascular system, with relatively little attention on skeletal muscle. Summary of current literature suggests that coffee has beneficial effects on skeletal muscle. Coffee has been shown to induce autophagy, improve insulin sensitivity, stimulate glucose uptake, slow the progression of sarcopenia, and promote the regeneration of injured muscle. Much more research is needed to reveal the full scope of benefits that coffee consumption may exert on skeletal muscle structure and function.

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.

Constitutive protein content of procaspases in murine tissue

Caspases are proteases most notably involved in apoptosis and inflammation. Although mRNA content is better described, the constitutive protein content of procaspases between tissue types is not well documented. Since mRNA and protein content do not necessarily correlate, we aimed to discern protein content differences between various tissues. Protein content of procaspase-1, -8, -9, and -12 was assessed in gastrocnemius, heart, liver, and kidney. Since highly expressed in skeletal muscle, content of procaspase-12 was also analyzed in muscles with different fiber type compositions to discern any fiber type differences. Furthermore, Western analysis for procaspase-12 revealed prominent bands of ∼40 kDa and ∼30 kDa under basal conditions, in addition to the 50 kDa band corresponding to the full-length procaspase. Therefore, the content of these caspase-12 related species in the tissue and muscle types is also described. Results show protein content of procaspase-1,-8, -9, and -12 and caspase-12 related species differs between tissue types and do not necessarily correlate with mRNA content reported in the published literature. Procaspase-12 content in skeletal muscle may be fiber-type dependent with higher expression in more oxidative fibers. Furthermore, the 40 kDa species of caspase-12 was the dominant form of the protein in most tissues analyzed.

Exercise is medicine: student pharmacists’ perceptions and knowledge of exercise prescription

With healthcare costs on the rise, a global initiative was launched in 2007, called Exercise is Medicine, to prescribe and counsel patients on exercise to aid in the prevention and treatment of chronic diseases. Since community pharmacists are one of the most accessible healthcare providers, this is an opportunity for pharmacists to also engage in this initiative. This study aimed to assess pharmacy student perceptions and knowledge on exercise to determine whether they are adequately prepared to counsel patients on exercise prescription. Third and fourth year pharmacy students were surveyed to test their basic knowledge of exercise prescription. Results show that 93.5% of students agreed or strongly agreed that it is important for pharmacists to counsel patients about exercise. The mean (SD) score for the 11 basic knowledge quiz questions on exercise prescription was 28.9% (SD 16.8), with no significant difference between third and fourth year pharmacy students. While students deemed exercise counseling as important, students proved deficient in exercise prescription knowledge. Schools of pharmacy may consider increasing curricular content to be congruent with this initiative.