title: Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-actin cross-bridge formation and kinetics.
abstract: Many patients with cancer experience physical disability following diagnosis, although little is known about the mechanisms underlying these functional deficits. To characterize skeletal muscle adaptations to cancer in humans, we evaluated skeletal muscle structure and contractile function at the molecular, cellular, whole-muscle, and whole-body level in 11 patients with cancer (5 cachectic, 6 noncachectic) and 6 controls without disease. Patients with cancer showed a 25% reduction in knee extensor isometric torque after adjustment for muscle mass (P < 0.05), which was strongly related to diminished power output during a walking endurance test (r = 0.889; P < 0.01). At the cellular level, single fiber isometric tension was reduced in myosin heavy chain (MHC) IIA fibers (P = 0.05) in patients with cancer, which was explained by a reduction (P < 0.05) in the number of strongly bound cross-bridges. In MHC I fibers, myosin-actin cross-bridge kinetics were reduced in patients, as evidenced by an increase in myosin attachment time (P < 0.01); and reductions in another kinetic parameter, myosin rate of force production, predicted reduced knee extensor isometric torque (r = 0.689; P < 0.05). Patients with cancer also exhibited reduced mitochondrial density (-50%; P < 0.001), which was related to increased myosin attachment time in MHC I fibers (r = -0.754; P < 0.01). Finally, no group differences in myofilament protein content or ultrastructure were noted that explained the observed functional alterations. Collectively, our results suggest reductions in myofilament protein function as a potential molecular mechanism contributing to muscle weakness and physical disability in human cancer.
authors: Department of Medicine, University of Vermont, College of Medicine, Burlington, VT, USA. michael.toth@uvm.edu
authors: Michael J
authors: MJ
authors: Toth
authors: Mark S
authors: MS
authors: Miller
authors: Damien M
authors: DM
authors: Callahan
authors: Andrew P
authors: AP
authors: Sweeny
authors: Ivette
authors: I
authors: Nunez
authors: Steven M
authors: SM
authors: Grunberg
authors: Hirak
authors: H
authors: Der-Torossian
authors: Marion E
authors: ME
authors: Couch
authors: Kim
authors: K
authors: Dittus
mesh_terms: D000199:Actins / Q000378:metabolism*; D000368:Aged; D005260:Female; D006801:Humans; D007537:Isometric Contraction; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology* / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications* / Q000503:physiopathology*
chemical_list: D000199:Actins; D018995:Myosin Heavy Chains