The Skeletal Muscle as an Active Player Against Cancer Cachexia

The management of cancer patients is frequently complicated by the occurrence of cachexia. This is a complex syndrome that markedly impacts on quality of life as well as on tolerance and response to anticancer treatments. Loss of body weight, wasting of both adipose tissue and skeletal muscle and reduced survival rates are among the main features of cachexia. Skeletal muscle wasting has been shown to depend, mainly at least, on the induction of protein degradation rates above physiological levels. Such hypercatabolic pattern is driven by overactivation of different intracellular proteolytic systems, among which those dependent on ubiquitin-proteasome and autophagy. Selective rather than bulk degradation of altered proteins and organelles was also proposed to occur. Within the picture described above, the muscle is frequently considered a sort of by-stander tissue where external stimuli, directly or indirectly, can poise protein metabolism toward a catabolic setting. By contrast, several observations suggest that the muscle reacts to the wasting drive imposed by cancer growth by activating different compensatory strategies that include anabolic capacity, the activation of autophagy and myogenesis. Even if muscle response is eventually ill-fated, its occurrence supports the idea that in the presence of appropriate treatments the development of cancer-induced wasting might not be an ineluctable event in tumor hosts

A Rat Immobilization Model Based on Cage Volume Reduction: A Physiological Model for Bed Rest?

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels –an indicator of a stress response– were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer

A rat immobilization model based on cage volume reduction: a physiological model for bed rest?

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels-an indicator of a stress response- were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC’s metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance

Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration

Cancer cachexia is a frequently neglected debilitating syndrome that, beyond representing a primary cause of death and cancer therapy failure, negatively impacts on patients’ quality of life. Given the complexity of its multisystemic pathogenesis, affecting several organs beyond the skeletal muscle, defining an effective therapeutic approach has failed so far. Revamped attention of the scientific community working on cancer cachexia has focused on mitochondrial alterations occurring in the skeletal muscle as potential triggers of the complex metabolic derangements, eventually leading to hypercatabolism and tissue wasting. Mitochondrial dysfunction may be simplistically viewed as a cause of energy failure, thus inducing protein catabolism as a compensatory mechanism; however, other peculiar cachexia features may depend on mitochondria. On the one side, chemotherapy also impacts on muscle mitochondrial function while, on the other side, muscle-impaired regeneration may result from insufficient energy production from damaged mitochondria. Boosting mitochondrial function could thus improve the energetic status and chemotherapy tolerance, and relieve the myogenic process in cancer cachexia. In the present work, a focused review of the available literature on mitochondrial dysfunction in cancer cachexia is presented along with preliminary data dissecting the potential role of stimulating mitochondrial biogenesis via PGC-1α overexpression in distinct aspects of cancer-induced muscle wasting

Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP