Cachectic skeletal muscle response to a novel bout of low-frequency stimulation

Abstract

While exercise benefits have been well documented in patients with chronic diseases, the mechanistic understanding of cachectic muscle's response to contraction is essentially unknown. We previously demonstrated that treadmill exercise training attenuates the initiation of cancer cachexia and the development of metabolic syndrome symptoms (Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, Carson JA. J Cachexia Sarcopenia Muscle 3: 117-137, 2012). However, cachectic muscle's metabolic signaling response to a novel, acute bout of low-frequency contraction has not been determined. The purpose of this study was to determine whether severe cancer cachexia disrupts the acute contraction-induced response to low-frequency muscle contraction [low-frequency stimulation (LoFS)]. Metabolic gene expression and signaling was examined 3 h after a novel 30-min bout of contraction (10 Hz) in cachectic Apc(Min/+) (Min) and C57BL/6 (BL-6) mice. Pyrrolidine dithiocarbamate, a STAT/NF-κB inhibitor and free radical scavenger, was administered systemically to a subset of mice to determine whether this altered the muscle contraction response. Although glucose transporter-4 mRNA was decreased by cachexia, LoFS increased muscle glucose transporter-4 mRNA in both BL-6 and Min mice. LoFS also induced muscle peroxisome proliferator-activated receptor-γ and peroxisome proliferator-activated receptor-α coactivator-1 mRNA. However, in Min mice, LoFS was not able to induce muscle proliferator-activated receptor-α coactivator-1 targets nuclear respiratory factor-1 and mitochondrial transcription factor A mRNA. LoFS induced phosphorylated-S6 in BL-6 mice, but this induction was blocked by cachexia. Administration of pyrrolidine dithiocarbamate for 24 h rescued LoFS-induced phosphorylated-S6 in cachectic muscle. LoFS increased muscle phosphorylated-AMP-activated protein kinase and p38 in BL-6 and Min mice. These data demonstrate that cachexia alters the muscle metabolic response to acute LoFS, and combination therapies in concert with muscle contraction may be beneficial for improving muscle mass and function during cachexia.

Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes

“…Exercise and repetitive muscle contractions also induce a transient activation of AMPK signaling (18). Interestingly, contracted cachectic muscle has an induction of AMPK signaling, which goes above an already elevated baseline level (50). Here, we report that the inhibition of myotube AMPK activity during LLC treatment can rescue suppressed mTORC1 signaling and protein synthesis.…”

“…Muscle contraction-induced mTORC1 signaling is attenuated in severely cachectic Apc Min/ϩ mice, which exhibit chronic activation of muscle STAT3 (50). Interestingly, PDTC administration to these cachectic mice can rescue contraction-induced mTORC1 activation (50). We found that both anabolic and catabolic stimuli can activate muscle NF-B signaling, which may be related to differential functions of NF-B in muscle as it relates to inflammatory and mechanical signals (28).…”

“…For example, anabolic resistance to amino acid and resistance exercise caused by either sarcopenia or sepsis is associated with NF-B activation (23). Muscle contraction-induced mTORC1 signaling is attenuated in severely cachectic Apc Min/ϩ mice, which exhibit chronic activation of muscle STAT3 (50). Interestingly, PDTC administration to these cachectic mice can rescue contraction-induced mTORC1 activation (50).…”

Role of interleukin-6 in cachexia

“…A large body of work in rodents has demonstrated that muscle wasting with cancer cachexia is a double edge sword that involves protein synthesis suppression and activation of several protein degradation pathways [23-26]. The Apc Min/+ and C26 tumor-implanted mice have an established IL-6 dependent loss of skeletal muscle during cancer cachexia[9, 27, 28].…”

“…In the cachectic Apc Min/+ mouse inhibition of IL-6 signaling through systemic administration of IL-6RAb attenuates further body weight and muscle loss without rescuing MPS. Additionally, the activation of mTOR signaling by both glucose and exercise is suppressed in the cachectic Apc Min/+ mouse [23, 26, 27]. However, this may be an indirect effect of IL-6, as IL-6 administration to C2C12 myotubes does not inhibit insulin stimulation of mTOR signaling [27].…”