PMID- 37378624
OWN - NLM
STAT- MEDLINE
DCOM- 20230712
LR  - 20230804
IS  - 1522-1555 (Electronic)
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 325
IP  - 2
DP  - 2023 Aug 1
TI  - Recovery from FOLFOX chemotherapy-induced systemic and skeletal muscle metabolic 
      dysfunction in mice.
PG  - E132-E151
LID - 10.1152/ajpendo.00096.2023 [doi]
AB  - FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is used to treat 
      colorectal cancer and can acutely induce metabolic dysfunction. However, the 
      lasting effects on systemic and skeletal muscle metabolism after treatment 
      cessation are poorly understood. Therefore, we investigated the acute and lasting 
      effects of FOLFOX chemotherapy on systemic and skeletal muscle metabolism in 
      mice. Direct effects of FOLFOX in cultured myotubes were also investigated. Male 
      C57BL/6J mice completed four cycles (acute) of FOLFOX or PBS. Subsets were 
      allowed to recover for 4 wk or 10 wk. Comprehensive Laboratory Animal Monitoring 
      System (CLAMS) metabolic measurements were performed for 5 days before study 
      endpoint. C2C12 myotubes were treated with FOLFOX for 24 hr. Acute FOLFOX 
      attenuated body mass and body fat accretion independent of food intake or cage 
      activity. Acute FOLFOX decreased blood glucose, oxygen consumption (V̇o(2)), 
      carbon dioxide production (V̇co(2)), energy expenditure, and carbohydrate (CHO) 
      oxidation. Deficits in V̇o(2) and energy expenditure remained at 10 wk. CHO 
      oxidation remained disrupted at 4 wk but returned to control levels after 10 wk. 
      Acute FOLFOX reduced muscle COXIV enzyme activity, AMPK(T172), ULK1(S555), and 
      LC3BII protein expression. Muscle LC3BII/I ratio was associated with altered CHO 
      oxidation (r = 0.75, P = 0.03). In vitro, FOLFOX suppressed myotube AMPK(T172), 
      ULK1(S555), and autophagy flux. Recovery for 4 wk normalized skeletal muscle AMPK 
      and ULK1 phosphorylation. Our results provide evidence that FOLFOX disrupts 
      systemic metabolism, which is not readily recoverable after treatment cessation. 
      FOLFOX effects on skeletal muscle metabolic signaling did recover. Further 
      investigations are warranted to prevent and treat FOLFOX-induced metabolic 
      toxicities that negatively impact survival and life quality of patients with 
      cancer.NEW & NOTEWORTHY The present study demonstrates that FOLFOX chemotherapy 
      induces long-lasting deficits in systemic metabolism. Interestingly, FOLFOX 
      modestly suppressed skeletal muscle AMPK and autophagy signaling in vivo and in 
      vitro. The FOLFOX-induced suppression of muscle metabolic signaling recovered 
      after treatment cessation, independent of systemic metabolic dysfunction. Future 
      research should investigate if activating AMPK during treatment can prevent 
      long-term toxicities to improve health and quality of life of patients with 
      cancer and survivors.
FAU - Halle, Jessica L
AU  - Halle JL
AUID- ORCID: 0000-0002-3174-5713
AD  - Integrative Muscle Biology Laboratory, Division of Regenerative and 
      Rehabilitation Sciences, College of Health Professions, University of Tennessee 
      Health Science Center, Memphis, Tennessee, United States.
FAU - Counts, Brittany R
AU  - Counts BR
AD  - Integrative Muscle Biology Laboratory, Division of Regenerative and 
      Rehabilitation Sciences, College of Health Professions, University of Tennessee 
      Health Science Center, Memphis, Tennessee, United States.
FAU - Paez, Hector G
AU  - Paez HG
AD  - Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, 
      College of Health Professions, University of Tennessee Health Science Center, 
      Memphis, Tennessee, United States.
FAU - Baumfalk, Dryden R
AU  - Baumfalk DR
AD  - Department of Applied Physiology & Kinesiology, University of Florida, 
      Gainesville, Florida, United States.
FAU - Zhang, Quan
AU  - Zhang Q
AD  - Integrative Muscle Biology Laboratory, Division of Regenerative and 
      Rehabilitation Sciences, College of Health Professions, University of Tennessee 
      Health Science Center, Memphis, Tennessee, United States.
FAU - Mohamed, Junaith S
AU  - Mohamed JS
AUID- ORCID: 0000-0002-1518-4856
AD  - Laboratory of Muscle and Nerve, Department of Diagnostic and Health Sciences, 
      College of Health Professions, University of Tennessee Health Science Center, 
      Memphis, Tennessee, United States.
FAU - Glazer, Evan S
AU  - Glazer ES
AD  - Department of Surgery, College of Medicine, University of Tennessee Health 
      Science Center, Memphis, Tennessee, United States.
FAU - Puppa, Melissa J
AU  - Puppa MJ
AD  - College of Health Sciences, The University of Memphis, Memphis, Tennessee, United 
      States.
FAU - Smuder, Ashley J
AU  - Smuder AJ
AD  - Department of Applied Physiology & Kinesiology, University of Florida, 
      Gainesville, Florida, United States.
FAU - Alway, Stephen E
AU  - Alway SE
AUID- ORCID: 0000-0002-0378-4707
AD  - Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, 
      College of Health Professions, University of Tennessee Health Science Center, 
      Memphis, Tennessee, United States.
FAU - Carson, James A
AU  - Carson JA
AD  - Integrative Muscle Biology Laboratory, Division of Regenerative and 
      Rehabilitation Sciences, College of Health Professions, University of Tennessee 
      Health Science Center, Memphis, Tennessee, United States.
LA  - eng
GR  - R01 HL146443/HL/NHLBI NIH HHS/United States
GR  - R21 CA231131/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230628
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - 0 (Antineoplastic Agents)
SB  - IM
MH  - Male
MH  - Animals
MH  - Mice
MH  - *AMP-Activated Protein Kinases/metabolism
MH  - Quality of Life
MH  - Mice, Inbred C57BL
MH  - Muscle, Skeletal/metabolism
MH  - *Antineoplastic Agents/metabolism
PMC - PMC10393342
OTO - NOTNLM
OT  - 5-FU
OT  - autophagy
OT  - carbohydrate oxidation
OT  - colorectal cancer
OT  - energy expenditure
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2023/06/28 13:08
MHDA- 2023/07/12 06:42
PMCR- 2024/08/01
CRDT- 2023/06/28 10:33
PHST- 2024/08/01 00:00 [pmc-release]
PHST- 2023/07/12 06:42 [medline]
PHST- 2023/06/28 13:08 [pubmed]
PHST- 2023/06/28 10:33 [entrez]
AID - E-00096-2023 [pii]
AID - 10.1152/ajpendo.00096.2023 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2023 Aug 1;325(2):E132-E151. doi: 
      10.1152/ajpendo.00096.2023. Epub 2023 Jun 28.