Diaphragm and ventilatory dysfunction during cancer cachexia

Abstract

Cancer cachexia is characterized by a continuous loss of locomotor skeletal muscle mass, which causes profound muscle weakness. If this atrophy and weakness also occurs in diaphragm muscle, it could lead to respiratory failure, which is a major cause of death in patients with cancer. Thus, the purpose of the current study was to determine whether colon-26 (C-26) cancer cachexia causes diaphragm muscle fiber atrophy and weakness and compromises ventilation. All diaphragm muscle fiber types were significantly atrophied in C-26 mice compared to controls, and the atrophy-related genes, atrogin-1 and MuRF1, significantly increased. Maximum isometric specific force of diaphragm strips, absolute maximal calcium activated force, and maximal specific calcium-activated force of permeabilized diaphragm fibers were all significantly decreased in C-26 mice compared to controls. Further, isotonic contractile properties of the diaphragm were affected to an even greater extent than isometric function. Ventilation measurements demonstrated that C-26 mice have a significantly lower tidal volume compared to controls under basal conditions and, unlike control mice, an inability to increase breathing frequency, tidal volume, and, thus, minute ventilation in response to a respiratory challenge. These data demonstrate that C-26 cancer cachexia causes profound respiratory muscle atrophy and weakness and ventilatory dysfunction.

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

“…These changes in function have the potential to cause muscle weakness and impair power generation by the muscle in vivo. Similar dysfunction has been reported for diaphragm preparations from mice with cancer cachexia (45). In this previous study, there was a reduction in the Ca 2ϩ sensitivity of force generation, the force of contraction, as well as the k tr in diaphragm preparations from cachexic CD2F1 mice (45).…”

“…Similar dysfunction has been reported for diaphragm preparations from mice with cancer cachexia (45). In this previous study, there was a reduction in the Ca 2ϩ sensitivity of force generation, the force of contraction, as well as the k tr in diaphragm preparations from cachexic CD2F1 mice (45). It was suggested that these changes in function were caused by a decrease in the number of strongly bound force-generating cross-bridges and/or less force was being generated per cross-bridge.…”

Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia

“…Treatment with the proteasome inhibitor MIG132 has been shown to alleviate cachexia by inhibiting MAFBx and MuRF-1, showing their involvement in wasting (44). The wasting phenotype does not involve a reduction in the total number of muscle fibers or altered force generation per unit of cross-sectional area (25,29), although others have reported a significant reduction of force/cross-sectional area in the murine C26 model (28) and in human patients (38). Skeletal muscles in some cachectic models are unable to generate new muscle cells due to the inability of satellite cells to mature into myoblasts (16).…”

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

“…Skeletal muscle atrophy and weakness accompany several pathophysiological conditions, including muscle disuse (D'Antona et al, 2003), aging (Gosselin et al, 1994;Larsson et al, 1997a;Larsson et al, 1997b;Lowe et al, 2001;Thompson and Brown, 1999), cancer (Roberts et al, 2013a;Roberts et al, 2013b) and chronic heart failure (Evans et al, 1995;Greutmann et al, 2011). The loss of skeletal muscle mass and impaired function during these conditions contribute to reduced physical performance and quality of life, prolonged hospital stays and enhanced mortality (Evans, 2010).…”