Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure

Abstract

Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N-acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline-induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF-cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non-cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin-proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF-κB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF-cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin-1, MURF-1, NF-κB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow- and fast-twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF-cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF-κB transcriptional activity in both muscles. Treatment of CHF-cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF-cachectic patients.

Phenotypic and metabolic features of mouse diaphragm and gastrocnemius muscles in chronic lung carcinogenesis: influence of underlying emphysema

“…Cachexia, characterized by severe body and muscle mass loss and systemic inflammation, negatively impacts the quality of life of the patients and is usually present in advanced stages of their disease. In animal models of cachexia and muscle wasting of different etiology (respiratory, cardiac and cancer-induced cachexia), similar features to those observed in patients have also been reported [6–11]. …”

“…Recent evidence reported by our group and others [3, 4, 6–20] has shown that several cellular and molecular mechanisms are clearly involved in the pathophysiology of muscle mass loss in patients with muscle wasting [3, 4, 16–20], as well as in different experimental models of cachexia [6–15]. The most relevant mechanisms are part of a cascade of events that lead to enhanced muscle protein breakdown [4, 16, 18], through several cellular signaling pathways [4, 16, 18], mitochondria respiratory chain dysfunction [6, 10, 14, 19, 21–23], systemic inflammation [4, 5, 24], muscle and systemic oxidative stress [4, 6, 16, 25–27], apoptosis [7], and autophagy [4, 28].…”

“…MyHC-I and MyHC-II isoforms were identified using anti-MyHC-I (clone MHC, Biogenesis Inc., Poole, England, UK) and anti-MyHC-II antibodies (clone MY-32, Sigma, Saint Louis, MO), respectively, according to previously published methodologies [4, 6–8, 18]. …”

“…The area fraction of normal and abnormal muscle was evaluated on 3 μm paraffin-embedded sections of the diaphragm and gastrocnemius muscles in all groups of mice following previously published methodologies [4, 6–8, 16]. …”

“…The most relevant mechanisms are part of a cascade of events that lead to enhanced muscle protein breakdown [4, 16, 18], through several cellular signaling pathways [4, 16, 18], mitochondria respiratory chain dysfunction [6, 10, 14, 19, 21–23], systemic inflammation [4, 5, 24], muscle and systemic oxidative stress [4, 6, 16, 25–27], apoptosis [7], and autophagy [4, 28]. Moreover, in patients with chronic obstructive pulmonary disease (COPD) and lung cancer (LC) [4, 24], landmark structural and ultrastructural abnormalities (sarcomere disruptions) were also demonstrated in the vastus lateralis, which were associated with a significant myosin heavy chain (MyHC) loss in those muscles [4, 17].…”