bims-musmir 2024-08-04 papers

Am J Physiol Cell Physiol. 2024 Jul 29.

The Utility of the Rodent Synergist Ablation Model in Identifying Molecular and Cellular Mechanisms of Skeletal Muscle Hypertrophy.

Benjamin I Burke, Ahmed Ismaeel, John J McCarthy.

Skeletal muscle exhibits remarkable plasticity to adapt to stimuli such as mechanical loading. The mechanisms that regulate skeletal muscle hypertrophy due to mechanical overload have been thoroughly studied. Remarkably, our understanding of many of the molecular and cellular mechanisms that regulate hypertrophic growth were first identified using the rodent synergist ablation (SA) model and subsequently corroborated in human resistance exercise training studies. To demonstrate the utility of the SA model, we briefly summarize the hypertrophic mechanisms identified using the model and the following translation of these mechanism to human skeletal muscle hypertrophy induced by resistance exercise training.

Keywords: mTOR signaling; microRNAs; protein synthesis; ribosome biogenesis; satellite cell fusion

DOI: https://doi.org/10.1152/ajpcell.00362.2024

Am J Physiol Cell Physiol. 2024 Jul 29.

Counterpoint to: The Utility of the Rodent Synergist Ablation Model in Identifying Molecular and Cellular Mechanisms of Skeletal Muscle Hypertrophy.

Michael D Roberts, Troy A Hornberger, Stuart M Phillips.

Keywords: skeletal muscle; synergist ablation

DOI: https://doi.org/10.1152/ajpcell.00405.2024

Free Radic Biol Med. 2024 Jul 26. pii: S0891-5849(24)00580-X. [Epub ahead of print]223 69-86

CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction.

Luz Marina Sánchez-Mendoza, Carlos Pérez-Sánchez, Cristina García-Caballero, Miguel Pérez-Rodríguez, Pilar Calero-Rodríguez, Beatriz Vellón-García, Juan Antonio Moreno, M Isabel Burón, Rafael de Cabo, José A González-Reyes, José M Villalba.

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR. However, the mechanisms involved in both interventions could be independent since key aspects of energy metabolism and tissue lipid profile do not coincide, and many of the changes induced by CR in mitochondrial abundance and dynamics in the liver and skeletal muscle could be counteracted by CYB5R3 overexpression. In this study, we sought to elucidate the impact of CR on key markers of metabolic status, mitochondrial function, and pro-oxidant/antioxidant balance in transgenic (TG) female mice overexpressing CYB5R3 compared to their WT littermates. In females fed ad libitum, CYB5R3 overexpression decreased fat mass, led to a preferred utilization of fatty acids as an energy source, upregulated key antioxidant enzymes, and boosted respiration both in skeletal muscle and liver mitochondria, supporting that CYB5R3 overexpression is phenotypic closer to CR in females than in males. Whereas some markers of mitochondrial biogenesis and dynamics were found decreased in TG females on CR, as also found for the levels of Estrogen Receptor α, mitochondrial abundance and activity were maintained both in skeletal muscle and in liver. Our results reveal overlapping metabolic adaptations resulting from the overexpression of CYB5R3 and CR in females, but a specific crosstalk occurs when both interventions are combined, differing from the adaptations observed in TG males.

Keywords: Calorie restriction; Cytochrome b(5) reductase; Liver; Mitochondria; Sexual dimorphism; Skeletal muscle

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.07.034

Am J Physiol Cell Physiol. 2024 Jul 29.

Response to: Counterpoint to: The Utility of the Rodent Synergist Ablation Model in Identifying Molecular and Cellular Mechanisms of Skeletal Muscle Hypertrophy.

Benjamin I Burke, Ahmed Ismaeel, Ferdinand von Walden, Kevin A Murach, John J McCarthy.

Keywords: hypertrophy; muscle; resistance training; synergist ablation

DOI: https://doi.org/10.1152/ajpcell.00418.2024

Am J Physiol Cell Physiol. 2024 Jul 29.

The Risks and Rewards of the Synergist Ablation Model in Skeletal Muscle Biology Research: Editorial Focus.

Anika L Syroid, Thomas J Hawke.

Keywords: editorial

DOI: https://doi.org/10.1152/ajpcell.00504.2024

Front Biosci (Landmark Ed). 2024 Jul 23. 29(7): 264

Neuronal CBP-1 is Required for Enhanced Body Muscle Proteostasis in Response to Reduced Translation Downstream of mTOR.

Santina Snow, Dilawar Ahmad Mir, Zhengxin Ma, Jordan Horrocks, Matthew Cox, Marissa Ruzga, Hussein Sayed, Aric N Rogers.

BACKGROUND: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation.
METHODS: This study uses genetic tools (transgenic Caenorhabditis elegans (C. elegans), RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions.
RESULTS: We use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1.
CONCLUSIONS: Low translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

Keywords: C. elegans; eIF4G; healthspan; ifg-1; lifespan; proteostasis; translation

DOI: https://doi.org/10.31083/j.fbl2907264

Acta Physiol (Oxf). 2024 Jul 30. e14208

Mitochondria can substitute for parvalbumin to lower cytosolic calcium levels in the murine fast skeletal muscle.

Lorenzo Marcucci, Leonardo Nogara, Marta Canato, Elena Germinario, Anna Raffaello, Michela Carraro, Paolo Bernardi, Laura Pietrangelo, Simona Boncompagni, Feliciano Protasi, Nazareno Paolocci, Carlo Reggiani.

AIM: Parvalbumin (PV) is a primary calcium buffer in mouse fast skeletal muscle fibers. Previous work showed that PV ablation has a limited impact on cytosolic Ca2+ ([Ca2+]cyto) transients and contractile response, while it enhances mitochondrial density and mitochondrial matrix-free calcium concentration ([Ca2+]mito). Here, we aimed to quantitatively test the hypothesis that mitochondria act to compensate for PV deficiency.
METHODS: We determined the free Ca2+ redistribution during a 2 s 60 Hz tetanic stimulation in the sarcoplasmic reticulum, cytosol, and mitochondria. Via a reaction-diffusion Ca2+ model, we quantitatively evaluated mitochondrial uptake and storage capacity requirements to compensate for PV lack and analyzed possible extracellular export.
RESULTS: [Ca2+]mito during tetanic stimulation is greater in knock-out (KO) (1362 ± 392 nM) than in wild-type (WT) (855 ± 392 nM), p < 0.05. Under the assumption of a non-linear intramitochondrial buffering, the model predicts an accumulation of 725 μmoles/Lfiber (buffering ratio 1:11 000) in KO, much higher than in WT (137 μmoles/Lfiber, ratio 1:4500). The required transport rate via mitochondrial calcium uniporter (MCU) reaches 3 mM/s, compatible with available literature. TEM images of calcium entry units and Mn2+ quenching showed a greater capacity of store-operated calcium entry in KO compared to WT. However, levels of [Ca2+]cyto during tetanic stimulation were not modulated to variations of extracellular calcium.
CONCLUSIONS: The model-based analysis of experimentally determined calcium distribution during tetanic stimulation showed that mitochondria can act as a buffer to compensate for the lack of PV. This result contributes to a better understanding of mitochondria's role in modulating [Ca2+]cyto in skeletal muscle fibers.

Keywords: calcium; mitochondria; mouse skeletal muscle fibers; parvalbumin; reaction–diffusion model

DOI: https://doi.org/10.1111/apha.14208