Wesley S. Haynie

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.

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.