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Dr. Stewart Lecker

Muscle Protein Breakdown in Cachexia

The Stewart Lecker laboratory is exploring the molecular mechanisms behind the muscle wasting. This maladaptive response is very common after muscle injury (e.g. motor neuron damage), but it is even more commonly seen in chronic illnesses such as uremia, end stage renal disease, cancer, sepsis and uncontrolled diabetes. While it is known that muscle wasting occurs because of increased muscle protein degradation, the enzymes involved in the process and the intracellular signaling events remain to be established.

Atrogenes and atrogin-1



One of our major recent contributions to this field has been to use gene microarray technology to define the spectrum of transcriptional changes in muscle common to a variety of muscle wasting conditions. These studies have identified a number of new genes turned on during wasting that we have termed atrogenes. This set of genes contains a plethora of exciting potential regulators of muscle cell size still to be studied. One particular gene that we have begun characterizing, which we named atrogin-1, is induced in all states where muscle atrophy occurs and is a central regulator in the process. The gene is a ubiquitin protein ligase (E3) required for atrophy in skeletal muscle, but probably more broadly, in reduction of cell size in cardiac and smooth muscle as well. In the process of this work, we have elucidated the major signaling pathway that activates atrogin-1 and muscle wasting (i.e. suppression of IGF-1 signaling in muscle). We are currently exploring the molecular functions of atrogin-1 using basic cell biological methods. In addition, we are working with the Cardiology Division at the Jamaica Plain VAMC to study the expression of atrogenes in humans with severe heart failure (and muscle wasting). This clinical study will be critical to extend the 'atrogene' concept to human populations.

Atrogin-1 and the myopathy caused by HMG CoA reductase inhibitors (statins) -In an exciting new direction, our laboratory has found that statin-induced muscle side effects are mediated by atrogin-1-dependent pathways. In cultured muscle cells as well as in zebrafish, if atrogin-1 is absent or suppressed, statin muscle toxicity is diminished. Since atrogin-1 activation appears to be at a nexus of pathways leading to both muscle atrophy and myopathy, inhibiting its action clearly has important implications for a broad range of human illnesses. We hope that a detailed understanding of its activation and mechanism of action will lead to rational inhibitory therapies. Further, given the variability of muscle phenotypes in patients treated with statins and in other forms of muscle wasting, we believe that polymorphims in the atrogin-1 gene will be critical to identify and may underlie some of these differences. As a result, another goal of our studies is to try to identify genetic differences in atrogin-1 among human populations prone to statin myopathy or muscle wasting.

Ultimately, it is hoped that an understanding of muscle protein breakdown on the molecular level will identify targets for development of drugs to combat this debilitating aspect of so many chronic illnesses.