PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia

Pin, Fabrizio; Novinger, Leah J.; Huot, Joshua R.; Harris, Robert A.; Couch, Marion E.; O’Connell, Thomas M.; Bonetto, Andrea

doi:10.1096/fj.201802799r

Cited by 48 publications

(71 citation statements)

References 65 publications

(116 reference statements)

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“…To understand the pathways that may potentially lead to this exacerbation, we performed RNA-seq on quadriceps muscles. We found that over 60% of genes altered in mC26 and C26 hosts were similar, including known prognosticators of muscle wasting such as STAT3, MurRF-1, Atrogin-1, FBXO31, and PDK4 (14,21,(39)(40)(41)52). However, the fold-change elevation of these genes tended to be generally greater in mC26 hosts (STAT3, 5.6 versus 4.6; MuRF-1, 25 versus 20; Atrogin-1, 14 versus 13.9; FBX031, 6 versus 6.2; PDK4, 8.7 versus 5.7), which may in part explain the worsened muscle wasting.…”

Section: Discussionmentioning

confidence: 89%

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

Huot¹,

Novinger²,

Pin³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 89%

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

Huot¹,

Novinger²,

Pin³

et al. 2020

JCI Insight

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“…Murine C2C12 skeletal myoblasts (ATCC, Manassas, VA) were grown in high glucose DMEM supplemented with 10% FBS, 100 U/ml penicillin, 100 mg/ml streptomycin, 100 mg/ml sodium pyruvate, 2 mM L-glutamine, and maintained at 37°C in 5% CO 2 , as shown in Pin et al (40). Myotubes were generated by exposing the myoblasts to DMEM containing 2% horse serum (i.e., differentiation medium, DM), and replacing the medium every other day for 5 days.…”

Section: Methodsmentioning

confidence: 99%

“…C2C12 cell layers were fixed in ice-cold acetone-methanol and incubated with an anti-Myosin Heavy Chain antibody (MF-20, 1:200; Developmental Studies Hybridoma Bank, Iowa City, IA) and an AlexaFluor 488-labeled secondary antibody (Invitrogen, Grand Island, NY), as reported in Pin et al (40). Analysis of myotube size was performed by measuring the minimum diameter of long, multi-nucleate fibers avoiding regions of clustered nuclei on a calibrated image using the Image J 1.43 software (42).…”

Section: Methodsmentioning

confidence: 99%

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

Essex

Huot

et al. 2019

Front. Endocrinol.

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Chemotherapy is frequently accompanied by several side effects, including nausea, diarrhea, anorexia and fatigue. Evidence from ours and other groups suggests that chemotherapy can also play a major role in causing not only cachexia, but also bone loss. This complicates prognosis and survival among cancer patients, affects quality of life, and can increase morbidity and mortality rates. Recent findings suggest that soluble factors released from resorbing bone directly contribute to loss of muscle mass and function secondary to metastatic cancer. However, it remains unknown whether similar mechanisms also take place following treatments with anticancer drugs. In this study, we found that young male CD2F1 mice (8-week old) treated with the chemotherapeutic agent cisplatin (2.5 mg/kg) presented marked loss of muscle and bone mass. Myotubes exposed to bone conditioned medium from cisplatin-treated mice showed severe atrophy (−33%) suggesting a bone to muscle crosstalk. To test this hypothesis, mice were administered cisplatin in combination with an antiresorptive drug to determine if preservation of bone mass has an effect on muscle mass and strength following chemotherapy treatment. Mice received cisplatin alone or combined with zoledronic acid (ZA; 5 μg/kg), a bisphosphonate routinely used for the treatment of osteoporosis. We found that cisplatin resulted in progressive loss of body weight (−25%), in line with reduced fat (−58%) and lean (−17%) mass. As expected, microCT bone histomorphometry analysis revealed significant reduction in bone mass following administration of chemotherapy, in line with reduced trabecular bone volume (BV/TV) and number (Tb.N), as well as increased trabecular separation (Tb.Sp) in the distal femur. Conversely, trabecular bone was protected when cisplatin was administered in combination with ZA. Interestingly, while the animals exposed to chemotherapy presented significant muscle wasting (~-20% vs. vehicle-treated mice), the administration of ZA in combination with cisplatin resulted in preservation of muscle mass (+12%) and strength (+42%). Altogether, these observations support our hypothesis of bone factors targeting muscle and suggest that pharmacological preservation of bone mass can benefit muscle mass and function following chemotherapy.

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“…Furthermore, pyruvate dehydrogenase kinase 4 (PDK4), an important metabolic regulator, is elevated in several atrophic conditions including cancer, starvation, diabetes, and sepsis. Overexpression of PDK4 in myotubes promotes myofiber atrophy and mitochondrial abnormalities, whereas its blockage rescues myotube size in cells exposed to tumor conditioned media [ 197 ].…”

Section: Metabolic Regulators Of Muscle Massmentioning

confidence: 99%

Signaling Pathways That Control Muscle Mass

Vainshtein¹,

Sandri

2020

IJMS

110

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The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research.

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PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia

Cited by 48 publications

References 65 publications

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia

Bisphosphonate Treatment Ameliorates Chemotherapy-Induced Bone and Muscle Abnormalities in Young Mice

Signaling Pathways That Control Muscle Mass

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