Molecular alterations in muscle wasting and cachexia : therapeutic approaches in animal models
Cachexia and muscle deconditioning, which are the major comorbidities in patients with chronic diseases including lung cancer (LC), impair disease prognosis. Several biological mechanisms are involved in these two muscle wasting conditions but current treatment options are limited. Hypothesis: the b...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2016 |
| Country: | España |
| Institution: | CBUC, CESCA |
| Repository: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/458880 |
| Online Access: | http://hdl.handle.net/10803/458880 |
| Access Level: | Open access |
| Keyword: | Cancer-induced cachexia Muscle disuse atrophy Muscla catabolism, damage and regeneration Therapeutic approaches Epigenetic events Caquexia cancerosa Atrofia muscular pos desuso Catabolismo, daño y regeneración del músculo Enfoques terapéuticos Mecanismos epigenéticos 616.2 |
| Summary: | Cachexia and muscle deconditioning, which are the major comorbidities in patients with chronic diseases including lung cancer (LC), impair disease prognosis. Several biological mechanisms are involved in these two muscle wasting conditions but current treatment options are limited. Hypothesis: the biological mechanisms involved in muscle wasting and dysfunction may differ between muscle deconditioning and LC induced cachexia in mice. We also hypothesized that the profile of molecular events implicated in disuse muscle atrophy and muscle recovery, may be different between early and late phases in gastrocnemius of mice exposed to hindlimb unloading. Pharmacological inhibition of MAPK, NF-kB, and proteasome, and the deficiency of either PARP-1 or PARP-2 proteins may revert impaired muscle mass and force in cachectic animals. Objectives: to explore the differences in the biological mechanisms potentially involved in muscle wasting and dysfunction in LC cancer cachexia and disuse muscle atrophy. To establish the temporal sequence of the molecular events involved in skeletal muscle mass loss during limb muscle unloading and reloading. To investigate several pharmacological strategies potentially beneficial for cachexia treatment. Methods: muscle mass, structure and function, muscle proteolysis, muscle anabolism, signaling pathways, and epigenetic markers were evaluated in 1) the diaphragm and gastrocnemius of LC cachectic mice: wild type, Parp-1-/- and Parp-2-/-; 2) in gastrocnemius of mice exposed to different periods of hindlimb immobilization and recovery. Results: In LC cachectic wild type mice: muscle proteolysis, MAPK, NF-κB, and protein acetylation were increased, while muscle structure and function, muscle anabolism, microRNAs, myogenic transcription factors and hystone deacetylases were decreased. After late-time points of hindlimb immobilization, muscle structure and function, and muscle anabolism were decreased, whereas FoxO signaling and proteolysis were increased. Muscle reloading improved the alterations seen during immobilization, especially during late phases. Pharmacological inhibition of NF-κB and MAPK, and PARP-1 and -2 deficiencies improved muscle mass and force through a decrease in protein oxidation and catabolism, together with a greater content of contractile and functional proteins. Conclusions: Molecular mechanisms involved in muscle mass loss and dysfunction are slightly different depending on the underlying condition (cancer or disuse). During disuse muscle atrophy, biological mechanisms are characterized by a differential expression profile between early- and late-phases, being the latter a crucial stage for muscle recovery. NF-κB and MAPK inhibitors, as well as available PARP inhibitors, may have potential clinical applicability for cancer cachexia treatment. |
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