MicroRNA expression and protein acetylation pattern in respiratory and limb muscles of Parp-1(-/-) and Parp-2(-/-) mice with lung cancer cachexia

Abstract

Background: Current treatment options for cachexia, which impairs disease prognosis, are limited. Muscle-enriched microRNAs and protein acetylation are involved in muscle wasting including lung cancer (LC) cachexia. Poly(ADP-ribose) polymerases (PARP) are involved in muscle metabolism. We hypothesized that muscle-enriched microRNA, protein hyperacetylation, and expression levels of myogenic transcription factors (MTFs) and downstream targets, muscle loss and function improve in LC cachectic Parp-1(−/−) and Parp-2(−/−) mice.

Methods: Body and muscle weights, grip strength, muscle phenotype, muscle-enriched microRNAs (miR-1, -133, -206, and -486), protein acetylation, acetylated levels of FoxO1, FoxO3, and PGC-1α, histone deacetylases (HDACs) including SIRT1, MTFs, and downstream targets (α-actin, PGC-1α, and creatine kinase) were evaluated in diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) wild type (WT), Parp-1(−/−) and Parp-2−/− mice.

Results: Compared to WT cachectic animals, in both respiratory and limb muscles of Parp-1(−/−) and Parp-2(−/−) cachectic mice: downregulation of muscle-specific microRNAs was counterbalanced especially in gastrocnemius of Parp-1(−/−) mice; increased protein acetylation was attenuated (improvement in HDAC3, SIRT-1, and acetylated FoxO3 levels in both muscles, acetylated FoxO1 levels in the diaphragm); reduced MTFs and creatine kinase levels were mitigated; body and muscle weights, strength, and muscle fiber sizes improved, while tumor weight and growth decreased.

Conclusions: These molecular findings may explain the improvements seen in body and muscle weights, limb muscle force and fiber sizes in both Parp-1(−/−) and Parp-2(−/−) cachectic mice.

General significance: PARP-1 and -2 play a role in cancer-induced cachexia, thus selective pharmacological inhibition of PARP-1 and -2 may be of interest in clinical settings.

Keywords: Cancer-induced cachexia; Muscle structure and function; Muscle-enriched microRNAs; Myogenic transcription factors; Parp-1(−/−) and Parp-2(−/−) mice; Protein hyperacetylation.