A 62-year-old man is evaluated for worsening cough, shortness of breath, and episodic hemoptysis over the past 6 months. The patient has also had a 15-kg (33-lb) weight loss over the same period without any change in his diet or activity level. He has a 50-pack-year smoking history and does not use alcohol or illicit drugs. BMI is 18 kg/m². The patient appears cachectic with temporal wasting and generalized loss of muscle mass. Chest x-ray reveals a large lung mass with mediastinal lymphadenopathy and pleural effusion. Which of the following cellular processes is most likely responsible for this patient's muscle loss?

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11ec160b_39f0_8cb3_9249_bbc0e865f3b0_MD0001_00 This patient who has a 50-pack-year smoking history and a mediastinal mass likely has muscle atrophy due to cancer-related cachexia. Cachexia is a hypermetabolic state driven by elevated pro-inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6), which stimulate the ubiquitin-proteasome pathway to degrade skeletal muscle proteins (eg, actin, myosin). The ubiquitin-proteasome pathway is the major eukaryotic mechanism for selective proteolysis (the destruction of targeted proteins). The addition of ubiquitin multimers to a target protein marks it for rapid destruction by the proteasome, whereby the protein is unfolded within the proteasome core and chopped into small oligopeptides. These oligopeptides can be further degraded by cytosolic peptidases into individual amino acids. Other proteolytic pathways play a less prominent role in the degradation of muscle tissue. Lysosomes, membrane-bound organelles that contain proteases and other digestive enzymes, are primarily tasked with breaking down extracellular components that are brought into the cell via endocytosis and with slowly recycling obsolete cytosolic organelles and debris. (Choice B) Necrosis is characterized by cellular injury and premature death due to external factors such as infection, toxin, or trauma. It is often characterized by irreparable damage to the cellular membrane with subsequent leakage of cellular contents. (Choice C) Both Duchenne and Becker muscular dystrophies are caused by X-linked mutations to the dystrophin gene. Dystrophin provides mechanical stability to muscle cells during contraction. Mutations are associated with membrane tears that allow calcium to enter the cell and cause myofiber damage. (Choice D) Telomeres are DNA-protein structures at the end of chromosomes that shorten with each cell division. When telomeres shorten beyond a certain point, the cell undergoes apoptosis or senescence. (Choice E) Reprogramming of undifferentiated mesenchymal cells (eg, connective tissue) is a form of metaplasia. Metaplasia is characterized by the substitution of one differentiated cell type for another differentiated cell type not normally found in that tissue (eg, bone formation in muscle tissue after muscle injury). Educational objective: The ubiquitin-proteasome pathway mediates targeted protein degradation, which allows for rapid disposal of unneeded intracellular proteins. In cancer-related cachexia, high levels of pro-inflammatory cytokines lead to increased ubiquitination of sarcomeric muscle proteins, which in turn leads to extensive skeletal muscle loss. __________ References: Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. (http://www.ncbi.nlm.nih.gov/pubmed/8948566)

A 62-Year-Old Man Is Evaluated for Worsening Cough, Shortness of Breath