scholarly journals Absence of insulin signalling in skeletal muscle is associated with reduced muscle mass and function: evidence for decreased protein synthesis and not increased degradation

AGE ◽  
2010 ◽  
Vol 32 (2) ◽  
pp. 209-222 ◽  
Author(s):  
Elaine D. O’Neill ◽  
John P. H. Wilding ◽  
C. Ronald Kahn ◽  
Holly Van Remmen ◽  
Anne McArdle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Insulin Signalling ◽  
And Function

scholarly journals mTORC1 signaling is not essential for the maintenance of muscle mass and function in adult sedentary mice

2019 ◽  
Author(s):  
Alexander S. Ham ◽  
Kathrin Chojnowska ◽  
Lionel A. Tintignac ◽  
Shuo Lin ◽  
Alexander Schmidt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Muscle Fibers ◽  
Protein Translation ◽  
Muscle Size ◽  
Mtorc1 Signaling ◽  
And Function

AbstractBackgroundThe balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signaling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signaling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established.MethodsWe conditionally ablated the gene coding for the mTORC1-essential component raptor in muscle fibers of adult mice (iRAmKO). We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with RAmKO mice, which lack raptor in developing muscle fibers. We also used polysome profiling and proteomics to assess protein translation and associated signaling in skeletal muscle of iRAmKO mice.ResultsAnalysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibers decreases, but slow-type fibers increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass, or muscle fiber area was detected up to 5 months post-raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates.ConclusionsRaptor depletion and hence complete inhibition of mTORC1 signaling in fully-grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signaling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

scholarly journals Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 237
Author(s):  
Guobin Li ◽  
Lan Zhang ◽  
Kaiting Ning ◽  
Baoqiang Yang ◽  
Francisca M. Acosta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Transgenic Mice ◽  
Muscle Mass ◽  
Muscle Protein ◽  
Contractile Force ◽  
Fast Twitch Muscle ◽  
And Function ◽  
Fast Twitch ◽  
Muscle Contractile

Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.

Maslinic acid activates mTORC1 and human TGR5 and induces skeletal muscle hypertrophy

2021 ◽  
Author(s):  
Shotaro Murata ◽  
Takashi Sasaki ◽  
Yuki Yamauchi ◽  
Makoto Shimizu ◽  
Ryuichiro Sato
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Mammalian Target Of Rapamycin ◽  
Standard Diet ◽  
Muscular Hypertrophy ◽  
Akt Inhibitor ◽  
Pentacyclic Triterpene ◽  
Maslinic Acid ◽  
C2c12 Skeletal Muscle Cells

ABSTRACT Maslinic acid, a naturally occurring pentacyclic triterpene in more than 30 plants (including olives), reportedly increases human muscle mass and muscle strength; however, the underlying molecular mechanism remains unknown. C57BL/6J mice were fed a standard diet or supplemented with 0.27% maslinic acid for 4 weeks, and their skeletal muscle mass was measured. Mice that consumed maslinic acid displayed significant increases in gastrocnemius and soleus muscle mass. Cultured mouse-C2C12 skeletal muscle cells were treated with mammalian target of rapamycin complex 1 (mTORC1) or protein kinase b (Akt) inhibitor, and protein synthesis was quantified. Maslinic acid accelerated protein synthesis via mTORC1 activation independent of Akt. Furthermore, maslinic acid activated human Takeda G protein-coupled receptor 5 (TGR5) more strongly than mouse TGR5, augmenting the expression of several genes related to muscular hypertrophy. Maslinic acid activated mTORC1 and human TGR5, implying its contribution to human muscular hypertrophy through these effects.

scholarly journals NEUROMUSCULAR CHANGES WITH AGING AND SARCOPENIA

2018 ◽  
pp. 1-3
Author(s):  
B.C. Clark
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Function ◽  
Skeletal Muscle Mass ◽  
The Past ◽  
Conceptual Definition ◽  
Age Related ◽  
Per Se ◽  
Definition Of ◽  
And Function

Sarcopenia was originally conceptualized as the age-related loss of skeletal muscle mass. Over the ensuing decades, the conceptual definition of sarcopenia has changed to represent a condition in older adults that is characterized by declining muscle mass and function, with “function” most commonly conceived as muscle weakness and/or impaired physical performance (e.g., slow gait speed). Findings over the past 15-years, however, have demonstrated that changes in grip and leg extensor strength are not primarily due to muscle atrophy per se, and that to a large extent, are reflective of declines in the integrity of the nervous system. This article briefly summarizes findings relating to the complex neuromuscular mechanisms that contribute to reductions in muscle function associated with advancing age, and the implications of these findings on the development of effective therapies.

scholarly journals Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

2001 ◽  
Vol 281 (1) ◽  
pp. R133-R139 ◽  
Author(s):  
S. E. Samuels ◽  
A. L. Knowles ◽  
T. Tilignac ◽  
E. Debiton ◽  
J. C. Madelmont ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Human Condition ◽  
Skeletal Muscle Protein ◽  
Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

scholarly journals Sarcopenia in women with hip fracture: A comparison of hormonal biomarkers and their relationship to skeletal muscle mass and function

2020 ◽  
Vol 6 (3) ◽  
pp. 139-145
Author(s):  
Ming Li Yee ◽  
Raphael Hau ◽  
Alison Taylor ◽  
Mark Guerra ◽  
Peter Guerra ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Hip Fracture ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
And Function

scholarly journals Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation

2018 ◽  
Vol 314 (5) ◽  
pp. R741-R751 ◽  
Author(s):  
Nobuki Moriya ◽  
Mitsunori Miyazaki
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Protein Synthesis ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Satellite Cells ◽  
Muscle Hypertrophy ◽  
Mtor Signaling ◽  
Skeletal Muscle Hypertrophy ◽  
Satellite Cell Proliferation

Skeletal muscle mass is determined by the net dynamic balance between protein synthesis and degradation. Although the Akt/mechanistic target of rapamycin (mTOR)-dependent pathway plays an important role in promoting protein synthesis and subsequent skeletal muscle hypertrophy, the precise molecular regulation of mTOR activity by the upstream protein kinase Akt is largely unknown. In addition, the activation of satellite cells has been indicated as a key regulator of muscle mass. However, the requirement of satellite cells for load-induced skeletal muscle hypertrophy is still under intense debate. In this study, female germline Akt1 knockout (KO) mice were used to examine whether Akt1 deficiency attenuates load-induced skeletal muscle hypertrophy through suppressing mTOR-dependent signaling and satellite cell proliferation. Akt1 KO mice showed a blunted hypertrophic response of skeletal muscle, with a diminished rate of satellite cell proliferation following mechanical overload. In contrast, Akt1 deficiency did not affect the load-induced activation of mTOR signaling and the subsequent enhanced rate of protein synthesis in skeletal muscle. These observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and that Akt1 plays a critical role in regulating satellite cell proliferation during load-induced muscle hypertrophy.

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