Eccentric contraction-induced myofiber growth in tumor-bearing mice

Abstract

Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low-frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc(Min/+) mice initiating cachexia (N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice (N = 9) served as wild-type controls. Apc(Min/+) mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment.

Tribbles 3 regulates protein turnover in mouse skeletal muscle

“…Sections were stained with hematoxylin and eosin according to a previous study [22, 23]. Fibers were analyzed by ImageJ 1.48v (National Institutes of Health, Bethesda, MD, USA).…”

The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin‐6

“…skeletal muscle metabolic dysfunction in both humans (Marzetti et al, 2017;Merlini, Bonaldo, & Marzetti, 2015) and murine models of cancer-induced wasting (Boland, Chourasia, & Macleod, 2013;Brown et al, 2017;Carson et al, 2016;Hardee et al, 2016). We have previously shown that 2 weeks of elevated circulating IL-6 decreased murine skeletal muscle mitochondrial protein expression, and loss of muscle gp130 signalling increased mitochondrial fission and reduced mitochondrial fusion in basal conditions Puppa et al, 2012Puppa et al, , 2014.…”

“…Systemic overexpression of IL‐6 can accelerate the loss of muscle mass in tumour‐bearing mice, but the effects of IL‐6 on skeletal muscle mass and function in tumour‐free mice remain inconclusive (Puppa et al., ; White et al., , ). Mitochondrial function has emerged as an intriguing regulator of inflammation‐induced skeletal muscle metabolic dysfunction in both humans (Marzetti et al., ; Merlini, Bonaldo, & Marzetti, ) and murine models of cancer‐induced wasting (Boland, Chourasia, & Macleod, ; Brown et al., ; Carson et al., ; Hardee et al., ). We have previously shown that 2 weeks of elevated circulating IL‐6 decreased murine skeletal muscle mitochondrial protein expression, and loss of muscle gp130 signalling increased mitochondrial fission and reduced mitochondrial fusion in basal conditions (Fix et al., ; Puppa et al., , ).…”

The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting

“…There is clear evidence that hindlimb myofibers from tumor bearing rodents undergo atrophy regardless of the succinate dehydrogenase activity level [26,36,37,49] . Regardless, mitochondria dysfunction is an established regulator of myofiber protein turnover [21,25] , and gaps remain in our understanding of whether the fiber metabolic phenotype can produce differential regulation of cellular muscle wasting processes.…”