Role of PARP activity in lung cancer‐induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype

Abstract

Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1 ) and Parp-2 mice. In diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing mice (wild type, Parp-1 , and Parp-2 ), PARP activity (ADP-ribose polymers, pADPr), redox balance, muscle fiber phenotype, apoptotic nuclei, tyrosine release, protein ubiquitination, muscle-specific E3 ligases, NF-κB signaling pathway, markers of muscle anabolism (Akt, mTOR, p70S6K, and mitochondrial DNA) were evaluated along with body and muscle weights, and limb muscle force. Compared to wild type cachectic animals, in both respiratory and limb muscles of Parp-1 and Parp-2 cachectic mice: cancer induced-muscle wasting characterized by increased PARP activity, protein oxidation, tyrosine release, and ubiquitin-proteasome system (total protein ubiquitination, atrogin-1, and 20S proteasome C8 subunit) were blunted, the reduction in contractile myosin and atrophy of the fibers was attenuated, while no effects were seen in other structural features (inflammatory cells, internal or apoptotic nuclei), and markers of muscle anabolism partly improved. Activation of either PARP-1 or -2 is likely to play a role in muscle protein catabolism via oxidative stress, NF-κB signaling, and enhanced proteasomal degradation in cancer-induced cachexia. Therapeutic potential of PARP activity inhibition deserves attention.

Muscle regeneration potential and satellite cell activation profile during recovery following hindlimb immobilization in mice

“…In all the study animals, food intake was measured daily, and food and water were supplied ad libitum for the entire duration of the immobilization or recovery periods. In all mice, body weight and limb strength were determined on day 0, and right at the end of the immobilization or recovery time‐points (day 7, as described above) using a scale and a grip strength meter (Bioseb, Vitrolles, France), respectively, as previously reported (Barreiro & Gea, ; Chacon‐Cabrera et al, , , ; Chacon‐Cabrera, Gea, et al, ; Chacon‐Cabrera, Mateu‐Jimenez, et al, ). In the two groups of animals, total body weight and limb strength gain variables were calculated as the percentage of the measurements performed at the end of the study period (7‐day I or 7‐day R) with respect to the same measurements obtained at baseline (day 0 or on day 7 following the immobilization protocol) in the 7‐day I and 7‐day R study groups, respectively.…”

Muscle Phenotype, Proteolysis, and Atrophy Signaling During Reloading in Mice: Effects of Curcumin on the Gastrocnemius

“…Our group and others have published extensively in the elucidation of the mechanisms that underlie the process of muscle wasting and impaired function. As such, in models of disuse muscle atrophy and wasting, a rise in the levels of markers of proteolysis, autophagy, apoptosis, oxidative stress, and epigenetic modifications have been shown in muscles of both patients [2,[6][7][8][9][10][11] and animals [12][13][14][16][17][18][19][20][21][22]. Additionally, alterations in the structure of the myofibers along with a reduction in their size have also been demonstrated in muscles following periods of inactivity [12][13][14][16][17][18][19][20][21][22].…”

“…As such, in models of disuse muscle atrophy and wasting, a rise in the levels of markers of proteolysis, autophagy, apoptosis, oxidative stress, and epigenetic modifications have been shown in muscles of both patients [2,[6][7][8][9][10][11] and animals [12][13][14][16][17][18][19][20][21][22]. Additionally, alterations in the structure of the myofibers along with a reduction in their size have also been demonstrated in muscles following periods of inactivity [12][13][14][16][17][18][19][20][21][22].The study of the kinetics of the pathophysiological and biological events whereby the loss of muscle mass takes place following periods of disuse is important [23][24][25]. In this regard, the sequence of the expression of markers of proteolysis, apoptosis, autophagy, signaling, of structural alterations and fiber type switches, and that of impaired function have already been described in previous investigations [23][24][25].Post-translational modifications of transcription factors that signal proteolytic activation in muscles were described in several models of muscle atrophy [24][25][26].…”

Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

“…Muscle protein wasting in both experimental and human cancer cachexia is driven by ubiquitin‐proteasome and autophagic‐lysosomal degradation (3). However, the negative nitrogen balance may also derive from reduced synthesis rates (4, 5), although differences may occur among distinct cancer types and stages (6, 7).…”