Megan E. Rosa-Caldwell

Moderate physical activity promotes basal hepatic autophagy in diet-induced obese mice

Obesity is a known risk factor for the development of hepatic disease; obesity-induced fatty liver can lead to inflammation, steatosis, and cirrhosis and is associated with degeneration of the mitochondria. Lifestyle interventions such as physical activity may ameliorate this condition. The purpose of this study was to investigate regulation of mitochondrial and autophagy quality control in liver following Western diet-induced obesity and voluntary physical activity. Eight-week-old C57BL/6J mice were fed a Western diet (WD) or normal chow (NC, control) for 4 weeks; afterwards, groups were divided into voluntary wheel running (VWR) or sedentary (SED) conditions for an additional 4 weeks. WD-SED animals had a median histology score of 2, whereas WD-VWR was not different from NC groups (median score 1). There was no difference in mRNA of inflammatory markers Il6 and Tnfa in WD animals. WD animals had 50% lower mitochondrial content (COX IV and Cytochrome C proteins), 50% lower Pgc1a mRNA content, and reduced content of mitochondrial fusion and fission markers. Markers of autophagy were increased in VWR animals, regardless of obesity, as measured by 50% greater LC3-II/I ratio and 40% lower p62 protein content. BNIP3 protein content was 30% less in WD animals compared with NC animals, regardless of physical activity. Diet-induced obesity results in derangements in mitochondrial quality control that appear to occur prior to the onset of hepatic inflammation. Moderate physical activity appears to enhance basal autophagy in the liver; increased autophagy may provide protection from hepatic fat accumulation.

Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice

Cancer cachexia is largely irreversible, at least via nutritional means, and responsible for 20–40% of cancer‐related deaths. Therefore, preventive measures are of primary importance; however, little is known about muscle perturbations prior to onset of cachexia. Cancer cachexia is associated with mitochondrial degeneration; yet, it remains to be determined if mitochondrial degeneration precedes muscle wasting in cancer cachexia. Therefore, our purpose was to determine if mitochondrial degeneration precedes cancer‐induced muscle wasting in tumour‐bearing mice.

Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia.

PGC‐1α4 gene expression is suppressed by the IL‐6—MEK—ERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury

PGC‐1α4 is a novel regulator of muscle hypertrophy; however, there is limited understanding of the regulation of its expression and role in many (patho)physiological conditions. Therefore, our purpose was to elicit signalling mechanisms regulating gene expression of Pgc1α4 and examine its response to (patho)physiological stimuli associated with altered muscle mass.

Skeletal muscle insulin resistance as a precursor to Diabetes: Beyond glucoregulation.

BACKGROUND Prevalence of Type 2 Diabetes Mellitus (T2DM) has reached pandemic levels in the Western societies. T2DM begins with the development of peripheral insulin resistance which prior research suggests may commonly originate within the skeletal muscle. A number of mechanisms have been proposed for the development of muscle insulin resistance including those of classical glucose handling, and also other cellular derangements observed in this disease which include mitochondrial degeneration, alterations in muscle protein turnover and early evidences for dysregulation of the microRNAs. The purpose of the current review is to examine the current findings on these latter aspects of mitochondrial maintenance, protein turnover and microRNA dysregulation along with the potential implications for these derangements in the development of insulin resistance and hence T2DM. We summarize multiple evidences for the degeneration of mitochondria and known elements of the processes regulating mitochondrial quality. Subsequently, we examine current findings of the alterations in muscle protein synthesis and autophagic protein degradation in T2DM and potential feedback of these systems onto canonical insulin signaling. Finally, evidences have emerged for the dysregulation of microRNAs in muscle insulin resistance. Of note early data point to several microRNAs altered by the insulin resistant state which exhibit relations to classic insulin signaling and the other processes discussed here. CONCLUSION Considering that T2DM may be initiated with muscle insulin resistance, improved understanding of the dysregulation of these metabolic parameters of skeletal muscle in the pathogenesis of T2DM may be key to developing efficacious therapeutic modalities to prevent and treat this condition.

Autophagy activation, not peroxisome proliferator‐activated receptor γ coactivator 1α, may mediate exercise‐induced improvements in glucose handling during diet‐induced obesity

What is the central question of this study? What are the individual and combined effects of muscle‐specific peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) overexpression and physical activity during high‐fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle‐specific PGC‐1α overexpression provides no protection against lipid‐overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC‐1α content, protects against high‐fat diet‐induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise‐induced protection from lipid overload.

A Transcriptomic Analysis of the Development of Skeletal Muscle Atrophy in Cancer-Cachexia in Tumor-Bearing Mice

Cancer-cachexia (CC) is a wasting condition directly responsible for 20-40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the postcachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations before wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis lung carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wk of age with tumor allowed to develop for 1, 2, 3, or 4 wk and compared with PBS-injected control. Muscle wasting was evident at 4 wk LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared with PBS animals with largest differences seen in 4 wk LLC, suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: mitochondrial dysfunction and protein ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.

Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice: Protein turnover in development of cancer-cachexia

Cancer cachexia occurs in approximately 80% of cancer patients and is a key contributor to cancer‐related death. The mechanisms controlling development of tumour‐induced muscle wasting are not fully elucidated. Specifically, the progression and development of cancer cachexia are underexplored. Therefore, we examined skeletal muscle protein turnover throughout the development of cancer cachexia in tumour‐bearing mice.

Cardiac hypertrophy in sarcopenic obese C57BL/6J mice is independent of Akt/mTOR cellular signaling

Abstract Sarcopenic obesity (SO) is the comorbidity of age‐related muscle wasting and obesity. SO increases the risk of heart disease, but little is known about the cellular signaling in cardiac muscle of SO individuals. Aim The purpose of this study was to identify key cellular signaling alterations in cardiac muscle of sarcopenic obese mice. Methods Thirty‐two, male C57BL/6J mice were randomly divided into lean and high‐fat fed groups and raised to 3–4 months (young) or 20–22 months (aged) of age. Hearts were extracted and processed for Western blot and qRT‐PCR analyses. Results Hearts of SO mice were 36–55% heavier than the young, obese or aged, lean groups. Markers downstream of Akt were not elevated in the SO group. p‐p38:p38 MAPK was higher with age, and a 2‐fold increase was observed in the obese vs. lean aged groups. pERK1/2:ERK1/2 MAPK was ˜50–70% lower in the SO cardiac muscle compared to the young, obese group. pAMPK:AMPK was 50%–66% lower in the SO cardiac muscle compared to the obese and lean, aged groups. mRNA abundance of TNF&agr; was ˜2.5‐fold higher in the SO group. Conclusion Cardiac hypertrophy in SO is likely pathogenic as evidenced by the alterations in MAPK and AMPK protein content and lack of activation in the Akt/mTOR pathway. HighlightsSarcopenic obesity is associated with exacerbated cardiac hypertrophy.Cardiac hypertrophy in SO mice was independent of Akt/mTOR signaling.Cardiac hypertrophy in SO mice was associated with elevated p38 MAPK.Markers of inflammation and fibrosis were elevated in hearts of SO mice.Markers of glycolytic metabolism and autophagy were elevated in hearts of SO mice.

Autophagy activation, not PGC-1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity

What is the central question of this study? What are the individual and combined effects of muscle‐specific peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) overexpression and physical activity during high‐fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle‐specific PGC‐1α overexpression provides no protection against lipid‐overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC‐1α content, protects against high‐fat diet‐induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise‐induced protection from lipid overload.