bims-musmir 2024-07-21 papers

Arthritis Rheumatol. 2024 Jul 17.

Skeletal muscle composition, power, and mitochondrial energetics in older men and women with knee osteoarthritis.

Giovanna Distefano, Stephanie Harrison, John Lynch, Thomas M Link, Philip A Kramer, Sofhia V Ramos, Theresa Mau, Paul M Coen, Lauren M Sparks, Bret H Goodpaster, Peggy M Cawthon, Jane A Cauley, Nancy E Lane.

OBJECTIVE: To investigate the overall and sex-specific relationship between presence and severity of knee osteoarthritis (KOA) with muscle composition, power, and energetics in older adults.
METHODS: Males and females (n=655, 76.1±4.9yrs; 57% females) enrolled in the Study of Muscle, Mobility and Aging (SOMMA) completed standing knee radiographs and knee pain assessments. Participants were divided into three groups by Kellgren-Lawrence grade (KLG) of KOA severity (0-1; 2, or 3-4). Outcome measures included whole-body muscle mass, thigh fat free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics.
RESULTS: Overall, presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (p trend<0.036). Sex-specific analysis revealed reduced energetics only in females with KOA (p trend<0.007) compared to females with no KOA. In models adjusted for age, sex, race, NSAIDS use, site/technician, physical activity, height, and abdominal adiposity participants with KLG 3-4 had greater MFI (0.008% (0.004, 0.011) and lower leg power (-51.56W (-74.03, -29.10)) and specific power (-5.38W/L (-7.31, -3.45)) than KLG 0-1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power and specific power.
CONCLUSION: Muscle health is associated with presence and severity of KOA and differs by sex. While muscle composition and power are lower in both males and females with KOA, regardless of pain status, mitochondrial energetics is reduced only in females.

DOI: https://doi.org/10.1002/art.42953

J Cachexia Sarcopenia Muscle. 2024 Jul 15.

Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates.

Andrew M Holwerda, Marlou L Dirks, Pierre-Andre Barbeau, Joy Goessens, Annemie Gijsen, Luc J C van Loon, Graham P Holloway.

BACKGROUND: Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis.
METHODS: We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT).
RESULTS: Neither oxidative phosphorylation nor H2O2 emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P < 0.05). In older men, only submaximal mitochondrial oxidative phosphorylation (corrected for mitochondrial content) was positively associated with myofibrillar protein synthesis rates during exercise training (r = 0.72, P < 0.05). However, changes in oxidative phosphorylation and H2O2 emission were not associated with changes in skeletal muscle mass following training (both P > 0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05).
CONCLUSIONS: Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.

Keywords: Aging; Muscle protein synthesis; Physical inactivity; Reactive oxygen species; Skeletal muscle

DOI: https://doi.org/10.1002/jcsm.13532

Am J Physiol Cell Physiol. 2024 Jul 16.

Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.

Thomas D Cardaci, Brandon N VanderVeen, Alexander R Huss, Brooke M Bullard, Kandy T Velazquez, Norma Frizzell, James A Carson, Robert L Price, E Angela Murphy.

Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. While its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular LD content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis Lung Carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n=20) were implanted with LLC cells [106] in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red o/lipid staining (tibialis anterior), and protein (gastrocnemius). LLC mice had a greater number (232%; p=0.006) and size (130%; p=0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; p=0.0109) and 'very high' oil-red O positive (178%; p=0.0002) fibers compared to controls and this was inversely correlated with fiber size (R2=0.5294; p<0.0001). Morphological analyses of LDs show increased elongation and complexity (aspect ratio: IMF: 9%, p=0.046) with decreases in circularity (circularity: SS: 6%, p=0.042) or roundness (roundness: Whole: 10%, p=0.033; IMF: 8%, p=0.038) as well as decreased LD-mitochondria touch (-15%; p=0.006), contact length (-38%; p=0.036), and relative contact (86%; p=0.004). Further, dysregulation in lipid metabolism (adiponectin, CPT-1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (p<0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.

Keywords: Lewis Lung Carcinoma; high-fat diet; lipid deposition; lipid metabolism; muscle wasting

DOI: https://doi.org/10.1152/ajpcell.00345.2024

bioRxiv. 2024 Jul 11. pii: 2024.07.08.602430. [Epub ahead of print]

Vcam1+ Fibro-adipogenic Progenitors Mark Fatty Infiltration in Chronic Limb Threatening Ischemia.

Qunsheng Dai, Changxin Wan, Yueyuan Xu, Kaileen Fei, Lindsey A Olivere, Brianna Garrett, Leo Akers, Derek Peters, James Otto, Christopher D Kontos, Zhiceng Ji, Yarui Diao, Kevin W Southerland.

Skeletal muscle health and function is a critical determinant of clinical outcomes in patients with peripheral arterial disease (PAD). Herein, we identify fatty infiltration, the ectopic deposition of adipocytes in skeletal muscle, as a histological hallmark of end-stage PAD, also known as chronic limb threatening ischemia (CLTI). Leveraging single cell transcriptome mapping in mouse models of PAD, we identify a pro-adipogenic mesenchymal stromal cell population marked by expression of Vcam1 (termed Vcam1+ FAPs) that expands in the ischemic limb. Mechanistically, we identify Sfrp1 and Nr3c1 as regulators of Vcam1+ FAP adipogenic differentiation. Loss of Sfrp1 and Nr3c1 impair Vcam1+ FAP differentiation into adipocytes in vitro . Finally, we show that Vcam1+ FAPs are enriched in human CLTI patients. Collectively, our results identify a pro-adipogenic FAP subpopulation in CLTI patients and provide a potential therapeutic target for muscle regeneration in PAD.

DOI: https://doi.org/10.1101/2024.07.08.602430

J Cachexia Sarcopenia Muscle. 2024 Jul 15.

Skeletal muscle p53-depletion uncovers a mechanism of fuel usage suppression that enables efficient energy conservation.

BACKGROUND: The ability of skeletal muscle to respond adequately to changes in nutrient availability, known as metabolic flexibility, is essential for the maintenance of metabolic health and loss of flexibility contributes to the development of diabetes and obesity. The tumour suppressor protein, p53, has been linked to the control of energy metabolism. We assessed its role in the acute control of nutrient allocation in skeletal muscle in the context of limited nutrient availability.
METHODS: A mouse model with inducible deletion of the p53-encoding gene, Trp53, in skeletal muscle was generated using the Cre-loxP-system. A detailed analysis of nutrient metabolism in mice with control and knockout genotypes was performed under ad libitum fed and fasting conditions and in exercised mice.
RESULTS: Acute deletion of p53 in myofibres of mice activated catabolic nutrient usage pathways even under ad libitum fed conditions, resulting in significantly increased overall energy expenditure (+10.6%; P = 0.0385) and a severe nutrient deficit in muscle characterized by depleted intramuscular glucose and glycogen levels (-62,0%; P < 0.0001 and -52.7%; P < 0.0001, respectively). This was accompanied by changes in marker gene expression patterns of circadian rhythmicity and hyperactivity (+57.4%; P = 0.0068). These metabolic changes occurred acutely, within 2-3 days after deletion of Trp53 was initiated, suggesting a rapid adaptive response to loss of p53, which resulted in a transient increase in lactate release to the circulation (+46.6%; P = 0.0115) from non-exercised muscle as a result of elevated carbohydrate mobilization. Conversely, an impairment of proteostasis and amino acid metabolism was observed in knockout mice during fasting. During endurance exercise testing, mice with acute, muscle-specific Trp53 inactivation displayed an early exhaustion phenotype with a premature shift in fuel usage and reductions in multiple performance parameters, including a significantly reduced running time and distance (-13.8%; P = 0.049 and -22.2%; P = 0.0384, respectively).
CONCLUSIONS: These findings suggest that efficient nutrient conservation is a key element of normal metabolic homeostasis that is sustained by p53. The homeostatic state in metabolic tissues is actively maintained to coordinate efficient energy conservation and metabolic flexibility towards nutrient stress. The acute deletion of Trp53 unlocks mechanisms that suppress the activity of nutrient catabolic pathways, causing substantial loss of intramuscular energy stores, which contributes to a fasting-like state in muscle tissue. Altogether, these findings uncover a novel function of p53 in the short-term regulation of nutrient metabolism in skeletal muscle and show that p53 serves to maintain metabolic homeostasis and efficient energy conservation.

Keywords: Energy conservation; Metabolic efficiency; Metabolic homeostasis; Metabolism; Skeletal muscle; p53

DOI: https://doi.org/10.1002/jcsm.13529

iScience. 2024 Jul 19. 27(7): 110241

The E3 ubiquitin ligase Nedd4L preserves skeletal muscle stem cell quiescence by inhibiting their activation.

Darren M Blackburn, Korin Sahinyan, Aldo Hernández-Corchado, Felicia Lazure, Vincent Richard, Laura Raco, Gabrielle Perron, René P Zahedi, Christoph H Borchers, Christoph Lepper, Hiroshi Kawabe, Arezu Jahani-Asl, Hamed S Najafabadi, Vahab D Soleimani.

Adult stem cells play a critical role in tissue repair and maintenance. In tissues with slow turnover, including skeletal muscle, these cells are maintained in a mitotically quiescent state yet remain poised to re-enter the cell cycle to replenish themselves and regenerate the tissue. Using a panomics approach we show that the PAX7/NEDD4L axis acts against muscle stem cell activation in homeostatic skeletal muscle. Our findings suggest that PAX7 transcriptionally activates the E3 ubiquitin ligase Nedd4L and that the conditional genetic deletion of Nedd4L impairs muscle stem cell quiescence, with an upregulation of cell cycle and myogenic differentiation genes. Loss of Nedd4L in muscle stem cells results in the expression of doublecortin (DCX), which is exclusively expressed during their in vivo activation. Together, these data establish that the ubiquitin proteasome system, mediated by Nedd4L, is a key contributor to the muscle stem cell quiescent state in adult mice.

Keywords: biochemistry; biological sciences; cell biology; natural sciences; stem cells research

DOI: https://doi.org/10.1016/j.isci.2024.110241

Acta Physiol (Oxf). 2024 Jul 18. e14203

A single bout of resistance exercise triggers mitophagy, potentially involving the ejection of mitochondria in human skeletal muscle.

Francisco Díaz-Castro, Mauro Tuñón-Suárez, Patricia Rivera, Javier Botella, Jorge Cancino, Ana María Figueroa, Juan Gutiérrez, Claudette Cantin, Louise Deldicque, Hermann Zbinden-Foncea, Joachim Nielsen, Carlos Henríquez-Olguín, Eugenia Morselli, Mauricio Castro-Sepúlveda.

AIM: The present study aimed to investigate the effects of a single bout of resistance exercise on mitophagy in human skeletal muscle (SkM).
METHODS: Eight healthy men were recruited to complete an acute bout of one-leg resistance exercise. SkM biopsies were obtained one hour after exercise in the resting leg (Rest-leg) and the contracting leg (Ex-leg). Mitophagy was assessed using protein-related abundance, transmission electron microscopy (TEM), and fluorescence microscopy.
RESULTS: Our results show that acute resistance exercise increased pro-fission protein phosphorylation (DRP1Ser616) and decreased mitophagy markers such as PARKIN and BNIP3L/NIX protein abundance in the Ex-leg. Additionally, mitochondrial complex IV decreased in the Ex-leg when compared to the Rest-leg. In the Ex-leg, TEM and immunofluorescence images showed mitochondrial cristae abnormalities, a mitochondrial fission phenotype, and increased mitophagosome-like structures in both subsarcolemmal and intermyofibrillar mitochondria. We also observed increased mitophagosome-like structures on the subsarcolemmal cleft and mitochondria in the extracellular space of SkM in the Ex-leg. We stimulated human primary myotubes with CCCP, which mimics mitophagy induction in the Ex-leg, and found that BNIP3L/NIX protein abundance decreased independently of lysosomal degradation. Finally, in another human cohort, we found a negative association between BNIP3L/NIX protein abundance with both mitophagosome-like structures and mitochondrial cristae density in the SkM.
CONCLUSION: The findings suggest that a single bout of resistance exercise can initiate mitophagy, potentially involving mitochondrial ejection, in human skeletal muscle. BNIP3L/NIX is proposed as a sensitive marker for assessing mitophagy flux in SkM.

Keywords: BNIP3L/NIX; mitochondria cristae; mitochondria dynamics; mitophagy

DOI: https://doi.org/10.1111/apha.14203