Dataset Information

Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia.

ABSTRACT: Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.

SUBMITTER: Ibebunjo C

PROVIDER: S-EPMC3554128 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia.

Ibebunjo Chikwendu C Chick Joel M JM Kendall Tracee T Eash John K JK Li Christine C Zhang Yunyu Y Vickers Chad C Wu Zhidan Z Clarke Brian A BA Shi Jun J Cruz Joseph J Fournier Brigitte B Brachat Sophie S Gutzwiller Sabine S Ma QiCheng Q Markovits Judit J Broome Michelle M Steinkrauss Michelle M Skuba Elizabeth E Galarneau Jean-Rene JR Gygi Steven P SP Glass David J DJ

Molecular and cellular biology 20121029 2

Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identifie ...[more]

PMID: 23109432

Similar Datasets

Project description:BackgroundOxidative stress and damage are associated with a number of ageing phenotypes, including age-related loss of muscle mass and reduced contractile function (sarcopenia). Our group and others have reported loss of neuromuscular junction (NMJ) integrity and increased denervation as initiating factors in sarcopenia, leading to mitochondrial dysfunction, generation of reactive oxygen species and peroxides, and loss of muscle mass and weakness. Previous studies from our laboratory show that denervation-induced skeletal muscle mitochondrial peroxide generation is highly correlated to muscle atrophy. Here, we directly test the impact of scavenging muscle mitochondrial hydrogen peroxide on the structure and function of the NMJ and muscle mass and function in a mouse model of denervation-induced muscle atrophy CuZnSOD (Sod1-/- mice, Sod1KO).MethodsWhole-body Sod1KO mice were crossed to mice with increased expression of human catalase (MCAT) targeted specifically to mitochondria in skeletal muscle (mMCAT mice) to determine the impact of reduced hydrogen peroxide levels on key targets of sarcopenia, including mitochondrial function, NMJ structure and function, and indices of muscle mass and function.ResultsFemale adult (~12-month-old) Sod1KO mice show a number of sarcopenia-related phenotypes in skeletal muscle including reduced mitochondrial oxygen consumption and elevated reactive oxygen species generation, fragmentation, and loss of innervated NMJs (P < 0.05), a 30% reduction in muscle mass (P < 0.05), a 36% loss of force generation (P < 0.05), and a loss of exercise capacity (305 vs. 709 m in wild-type mice, P < 0.05). Muscle from Sod1KO mice also shows a 35% reduction in sarco(endo)plasmic reticulum ATPase activity (P < 0.05), changes in the amount of calcium-regulating proteins, and altered fibre-type composition. In contrast, increased catalase expression in the mMCAT × Sod1KO mice completely prevents the mitochondrial and NMJ-related phenotypes and maintains muscle mass and force generation. The reduction in exercise capacity is also partially inhibited (~35%, P < 0.05), and the loss of fibre cross-sectional area is inhibited by ~50% (P < 0.05).ConclusionsTogether, these striking findings suggest that scavenging of mitochondrial peroxide generation by mMCAT expression efficiently prevents mitochondrial dysfunction and NMJ disruption associated with denervation-induced atrophy and weakness, supporting mitochondrial H2 O2 as an important effector of NMJ alterations that lead to phenotypes associated with sarcopenia.

Project description:Purpose: Despite demonstrating that the overall effect of long-term rapamycin-treatment is overwhelmingly positive in aging skeletal muscle, we observed muscle-specificity in the responsiveness to rapamycin, leading us to hypothesize that the primary drivers of age-related muscle loss and therefore effective intervention strategies may differ between muscles. To address this question and dissect the key signaling nodes associated with mTORC1-driven muscle aging, we created a comprehensive multi-muscle gene expression atlas in adult, sarcopenic and rapamycin-treated mice using RNA-seq. Methods: To examine the impact of long-term rapamycin treatment, male C57BL/6 mice were fed encapsulated rapamycin incorporated into a standardized AIN93M diet at 42 ppm (i.e. mg per kg of food), corresponding to a dose of ~4 mg·kg-1·day-1, from 15- to 30-months of age. This dose of rapamycin has been shown to extend lifespan maximally in male C57BL/6 mice. We performed RNA-seq on gastrocnemius (GAS), tibialis anterior (TA), triceps brachii (TRI) and soleus (SOL) muscles from each of six mice for 10m, 30m and 30mRM groups. The four muscle types were chosen to encompass fore- and hindlimb locations (e.g. TRI and GAS); slow and fast contraction properties (e.g. SOL and GAS); anterior and posterior positioning (e.g. TA and GAS) and the extent of protection by rapamycin (TA and TRI: protected; SOL: partiallly protected; GAS: not protected). Results: Age-related gene expression changes were remarkably consistent across the four different muscles, varying only in magnitude. Despite having the smallest age-related muscle loss of the four muscles, TA had the strongest age-related gene expression response which was associated with an increased reinnervation response. Despite the strong between-muscle commonality of age-related changes, gene expression responses to prolonged rapamycin treatment differed substantially between muscles. Rapamycin partially reversed many age-related changes in mRNA expression in the TA and TRI, but not in SOL or GAS muscle. Principle component analysis (PCA) showed that rapamycin had common 'anti-aging' effects on all muscles, while also exerting muscle-specific pro-aging effects on muscles not protected by rapamycin. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.

Dataset Information

Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia.

Publications

Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets