The Role of AMPK in Regulating Muscle Mass and Function in Cancer Cachexia

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PROJECT SUMMARY/ABSTRACT Cancer cachexia (CC) is a wasting syndrome characterized by decreased appetite, weight loss, and muscle wasting in cancer patients leading to decreased physical function and poor quality of life, shortened lifespan, and higher medical costs. To this date, there is no approved treatment for CC. Paradoxically, muscle wasting and weakness are also very common side effects of some chemotherapeutic agents such as cisplatin, a first-line therapy for several cancer types. Since current interventions for preventing or treating cachexia associated with cancer or cisplatin are suboptimal, there is an urgent need to develop new therapies to improve muscle mass and function in these conditions. 5’-adenosine monophosphate-activated protein kinase (AMPK) is an intracellular energy sensor that plays a central role in skeletal muscle physiology through the regulation of mitochondrial biogenesis and metabolism. It has also been shown to decrease inflammation in a variety of cell types. AMPK is of particular interest in the context of CC because, although the mechanisms underlying cancer cachexia are not fully understood, one of the primary triggers of CC is increased inflammation and oxidative stress. Impaired mitochondrial function is also thought to be one of the main contributors to muscle dysfunction in CC. However, the function of AMPK in CC, as well as its potential therapeutic role in preventing muscle wasting and weakness are not known. This study aims to characterize the role of AMPK in cisplatin- and lung cancer tumor (Lewis Lung Carcinoma, LLC)- induced CC, and evaluate the potential for modulating AMPK as a therapeutic target for these conditions. Specific Aim 1A will investigate if genetic (AMPKα2 activity inhibited) or pharmacological inhibition of AMPK (Compound C) exacerbates cisplatin-induced muscle wasting and dysfunction in mice; whereas promoting AMPK activation by its agonist AICAR attenuates this myopathy. Specific Aim 1B will determine whether activating AMPK attenuates cisplatin-induced myopathy in C2C12 myotubes and characterize the signaling pathways involved. Specific Aim 2A will determine if AICAR attenuates LLC tumor-induced muscle wasting and dysfunction and Compound C exacerbates these deficits, and Specific Aim 2B will determine the same effects of AMPK modification on LLC media-cocultured C2C12 myotubes and elucidate the underlying molecular pathways. The overall hypothesis is that AMPK is essential for maintaining muscle function during cachexia; promoting AMPK activation by AICAR counteracts cisplatin- or tumor-induced muscle wasting and weakness, whereas inhibiting AMPK activation will exacerbate this myopathy. We postulate that the effects of AMPK are mediated by suppressing inflammation and oxidative stress while promoting mitochondrial function. Ultimately, our findings from this study will provide evidence of the potential therapeutic role of AMPK in CC, and benefit cancer patients by improving their quality of life and longevity. This project will also allow me to transit to an independent investigator in cancer cachexia and muscle research.