Satellite cells in human skeletal muscle; from birth to old age

Changes in satellite cell content play a key role in regulating skeletal muscle growth and atrophy. Yet, there is little information on changes in satellite cell content from birth to old age in humans. The present study defines muscle fiber type-specific satellite cell content in human skeletal muscle tissue over the entire lifespan. Muscle biopsies were collected in 165 subjects, from different muscles of children undergoing surgery (<18 years; n = 13) and from the vastus lateralis muscle of young adult (18–49 years; n = 50), older (50–69 years; n = 53), and senescent subjects (70–86 years; n = 49). In a subgroup of 51 aged subjects (71 ± 6 years), additional biopsies were collected after 12 weeks of supervised resistance-type exercise training. Immunohistochemistry was applied to assess skeletal muscle fiber type-specific composition, size, and satellite cell content. From birth to adulthood, muscle fiber size increased tremendously with no major changes in muscle fiber satellite cell content, and no differences between type I and II muscle fibers. In contrast to type I muscle fibers, type II muscle fiber size was substantially smaller with increasing age in adults (r = −0.56; P < 0.001). This was accompanied by an age-related reduction in type II muscle fiber satellite cell content (r = −0.57; P < 0.001). Twelve weeks of resistance-type exercise training significantly increased type II muscle fiber size and satellite cell content. We conclude that type II muscle fiber atrophy with aging is accompanied by a specific decline in type II muscle fiber satellite cell content. Resistance-type exercise training represents an effective strategy to increase satellite cell content and reverse type II muscle fiber atrophy.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-013-9583-2) contains supplementary material, which is available to authorized users.     

Skeletal muscle apoptosis, sarcopenia and frailty at old age

The loss of muscle mass and strength with aging, also referred to as sarcopenia of aging, is a highly prevalent condition among older adults and predicts several adverse outcomes, including disability, institutionalization and mortality. Although the exact mechanisms underlying sarcopenia are far to be unveiled, accumulating preclinical evidence suggests that an age-related acceleration of myocytes loss via apoptosis might represent a key mechanism driving the onset and progression of muscle loss. Furthermore, increased levels of apoptosis have also been reported in old rats undergoing acute muscle atrophy subsequent to muscle unloading, a condition that mimics the muscle loss observed during prolonged bed rest. Notably, preliminary evidence seems to confirm a causative role for apoptosis in age-related muscle loss in human subjects. Several signaling pathways of skeletal muscle apoptosis are currently under intense investigation, with a particular focus on the role played by mitochondria. Here, we will review the most recent evidence regarding various pathways of muscle apoptosis and their modulation by several interventions (caloric restriction, physical exercise, muscle unloading).     

Skeletal muscle in critical illness

Summary Skeletal muscle protein breakdown is a dominant feature of critical illness and is believed to be a useful biological response to injury. However the loss of muscle is accompanied by some major difficulties in medical management and complications for the patient. Protein turnover is difficult to study and the catabolic state is resistant to treatment, whether by nutritional or other strategies. This article provides an overview of the current physiological knowledge in this area, questions the usefulness of the catabolic response and highlights some new research worthy of further investigation. Received: 24 September 1998 Accepted: 20 April 1999     

Endocrine effects of growth hormone overexpression in transgenic coho salmon

Non-transgenic (wild-type) coho salmon (Oncorhynchus kisutch), growth hormone (GH) transgenic salmon (with highly elevated growth rates), and GH transgenic salmon pair fed a non-transgenic ration level (and thus growing at the non-transgenic rate) were examined for plasma hormone concentrations, and liver, muscle, hypothalamus, telencephalon, and pituitary mRNA levels. GH transgenic salmon exhibited increased plasma GH levels, and enhanced liver, muscle and hypothalamic GH mRNA levels. Insulin-like growth factor-I (IGF-I) in plasma, and growth hormone receptor (GHR) and IGF-I mRNA levels in liver and muscle, were higher in fully fed transgenic than non-transgenic fish. GHR mRNA levels in transgenic fish were unaffected by ration-restriction, whereas plasma GH was increased and plasma IGF-I and liver IGF-I mRNA were decreased to wild-type levels. These data reveal that strong nutritional modulation of IGF-I production remains even in the presence of constitutive ectopic GH expression in these transgenic fish. Liver GHR membrane protein levels were not different from controls, whereas, in muscle, GHR levels were elevated approximately 5-fold in transgenic fish. Paracrine stimulation of IGF-I by ectopic GH production in non-pituitary tissues is suggested by increased basal cartilage sulphation observed in the transgenic salmon. Levels of mRNA for growth hormone-releasing hormone (GHRH) and cholecystokinin (CCK) did not differ between groups. Despite its role in appetite stimulation, neuropeptide Y (NPY) mRNA was not found to be elevated in transgenic groups.     

Type 2 deiodinase expression is stimulated by growth factors in human vascular smooth muscle cells

Type 2 deiodinase (D2) catalyzes the conversion of the prohormone T4 to the biologically active T3. D2 is expressed in human aortic smooth muscle cells (hASMCs). In this study, we demonstrated that the D2 mRNA and activity in hASMCs were up-regulated by platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (bFGF). The induction of D2 mRNA by PDGF-BB and bFGF was dependent on de novo RNA and protein synthesis. PD98059, a specific inhibitor of the upstream kinase that activates extracellular signal-regulated kinase (ERK), significantly suppressed the induction by both PDGF-BB and bFGF. SB203580, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, and SP600125, a specific inhibitor of c-Jun N-terminal kinase (JNK), also reduced the induction by both PDGF-BB and bFGF. These results suggest that both PDGF-BB and bFGF induce D2 expression at least partly via ERK pathway. The p38 MAP kinase and JNK pathways may also be involved in the induction.     

Skeletal muscle glucose transporter gene expression is not affected by injecting growth-hormone-secreting cells in young rats

Summary To elucidate the diabetogenic effect of growth hormone on glucose metabolism the regulation of glucose transporter (GLUT) gene expression was examined in rat skeletal muscles. Female Wistar-Furth rats were implanted subcutaneously with growth-hormone-producing pituitary tumour (GH₃) cells. Animals were killed 4 or 9 weeks after GH₃ cell injection. Although body weight, serum growth hormone and insulin-like growth factor I levels were remarkably elevated during the 4–9 week period, serum blood glucose levels were within normal range. Muscles were obtained from the quadriceps muscle, diaphragm and heart, respectively. Northern blot analysis and Western blot analysis were performed using specific cDNA probes and antibodies. During the 4–9 week period, the levels of muscle GLUT 1 and 4 mRNA (corrected by β-actin mRNA level) in each muscle from the rats injected with tumour cells were not significantly different from those of control rats. Chronic elevation of growth hormone in these rats did not cause any change in GLUT1 and 4 expression compared to the controls during the euglycaemic period. These results provide the first evidence that chronic growth hormone elevation itself does not affect a key gene of in vivo glucose metabolism.     

肾上腺疾病中的骨骼肌胰岛素抵抗现象

多种肾上腺疾病存在骨骼肌胰岛素抵抗(IR)现象.醛固酮通过影响胰岛素受体功能和信号转导,或通过诱导氧化应激导致骨骼肌IR;糖皮质激素干扰胰岛素信号和糖原合成,或促进脂肪分解,减少骨骼肌胰岛素介导的葡萄糖摄取;儿茶酚胺诱导或加重骨骼肌IR,可能与血清脂联素水平下降有关;肾上腺偶发瘤患者骨骼肌IR发生率增加,这可能与亚临床...     

辛伐他汀对大鼠平滑肌祖细胞和内皮祖细胞分化的不同影响

目的：观察辛伐他汀对平滑肌祖细胞（SPC）和内皮祖细胞（EPC）分化的影响。方法：采用密度梯度离心法获取大鼠骨髓单个核细胞,将其接种在纤维连接素包被培养板,加入不同浓度辛伐他汀（0．01～10μmol／L）培养8d。采用平滑肌肌动蛋白免疫荧光染色鉴定骨髓源性SPC,激光共聚焦显微镜鉴定FITC—UEA—I和Di I-acLDL双染阳性细胞为正在分化的EPC,并在倒置荧光显微镜下计数。结果：辛伐他汀显著抑制骨髓单个核细胞分化为SPC。0．01μmol／L辛伐他汀组与对照组SPC数量分别为79±5对85±4（P〈0．05）。辛伐他汀显著促进骨髓单个核细胞向EPC分化,其促进作用随辛伐他汀浓度升高而增加,在1．0μmol／L达最大效应。1μmol／L辛伐他汀组与对照组EPC数量分别为87±5对39±4（P〈0．01）。结论：辛伐他汀选择性抑制骨髓单个核细胞向SPC分化,促进其向EPC分化,局部应用有促进损伤血管再内皮化和抑制新生内膜过度增生的可能。     

Differential gene expression induced by growth hormone treatment in the uremic rat growth plate

OBJECTIVES: Treatment with growth hormone (GH) improves growth retardation of chronic renal failure. cDNA microarrays were used to investigate GH-induced modifications in gene expression in the tibial growth plate of young rats. DESIGN: RNA was extracted from the tibial growth plate from two groups, untreated and treated with GH, of young rats made uremic by subtotal nephrectomy (n=10). To validate changes shown by the Agilent oligo microarrays, some modulated genes known to play a physiological role in growth plate metabolism were analyzed by real-time quantitative polymerase chain reaction (qPCR). RESULTS: The microarrays showed that GH modified the expression of 224 genes, 195 being upregulated and 29 downregulated. qPCR results confirmed the sense of expression change found in the arrays for insulin-like growth factor I, insulin-like growth factor II, collagen V alpha 1, bone morphogenetic protein 3 and proteoglycan type II. CONCLUSIONS: This study shows for the first time the profile of growth plate gene expression modifications caused by GH treatment in experimental uremia and provides a basis to further investigate selected individual genes with potential implication in the stimulating effect on the growth of GH treatment in chronic renal failure.     

The relationship between masseter muscle thickness and appendicular skeletal muscle mass in Japanese community-dwelling elders: A cross-sectional study

Purpose of the studySarcopenia has been identified as a health hazard in elderly people. Although the association between sarcopenia and a decrease in masticatory function has been reported, the mechanism underlying this association has not been widely reported. Therefore, in order to elucidate the relationship between sarcopenia and masticatory function, we examined whether the masseter muscle thickness (MMT), which is a factor influencing masticatory function, in community-dwelling elders is associated with the appendicular skeletal muscle index (SMI), a diagnostic criterion for sarcopenia.Materials and methodsMMT was measured in 774 community-dwelling elders aged 65 years or older at resting state via ultrasonography, and SMI was measured with the bioelectrical impedance method. The relationships were investigated by calculating Pearson's correlation coefficients. Multiple regression analyses adjusted for age and sex, SMI, and oral-related items were performed to determine the association between these factors.ResultsThere was a significant correlation between the MMT and the SMI. The multiple regression analysis indicated that SMI was significantly associated with a decrease in MMT.ConclusionsThe reduction in whole-body skeletal muscle mass in sarcopenia may be involved in the reduction in MMT. Prevention of sarcopenia may be an important factor for maintaining masticatory function in the elderly.     

Stimulation of mitogen-activated protein kinase pathway in rat somatotrophs by growth hormone-releasing hormone

Growth hormone-releasing hormone (GHRH) is an important regulator of somatotroph development and function. However, GHRH signaling is still not completely understood. Signaling through the mitogen-activated protein kinase (MAPK) pathway has been observed in a wide variety of cell types but has not been explored as a mediator of GHRH action. In this study, we examined the phosphorylation of MAPK pathway intermediates in response to GHRH. After treatment of the GH4 rat somatotroph cell line with rGHRH (10⁷ M) for 2.5 min, there was robust phosphorylation of MAPK not seen in vehicle-treated cells. Treatment of HeLa cells with GHRH resulted in no activation of MAPK, but activation was conferred by transfection with the GHRH receptor cDNA. MAPK activation by GHRH was dose dependent from 1 to 100 nM, was evident at 2.5 min, peaked at 5 min, and returned to baseline by 20 min. Pretreatment of GH4 cells with somatostatin analog BIM23014 or the MEK1 inhibitor PD98095 prevented the activation of MAPK. Finally, treatment with GHRH increased GH4 proliferation in culture, and this response was prevented by pretreatment with BIM 23014 and PD98095. These results indicate that GHRH activates the MAPK pathway. Furthermore, activation of MAPK may mediate, at least in part, the effects of GHRH on somatotroph cell line proliferation. The findings support the concept that multiple pathways mediate the effects of GHRH.     

Skeletal muscle endurance and muscle metabolism in patients with chronic heart failure

BACKGROUND: Alterations in skeletal muscle function are known to contribute to exercise intolerance in patients with chronic heart failure (CHF). OBJECTIVES: To evaluate whether muscle isometric endurance can be objectively measured and whether it is related to skeletal muscle metabolism in CHF. METHODS: Isometric endurance of the vastus lateralis, measured as time to fatigue (T(F)), was evaluated in 25 patients with CHF (55+/-8 years of age [mean +/- SD]) and 18 healthy subjects (HS) (62+/-6 years of age [mean +/- SD]). Median frequency of surface electromyography was obtained from spectral analysis using a fast Fourier transformation. Citrate synthase (CS), 3-hydroxyacyl-CoA dehydrogenase (HADH), hexokinase (HK) and phosphofructokinase (PFK) activities were determined from the right vastus lateralis muscle. RESULTS: T(F) was lower in CHF patients than in HS (49+/-4 s and 80+/-7 s, respectively; P<0.01). Muscle fatigue was present at the end of the endurance test in both groups (median frequency breakpoint at mid-exercise for both groups [P<0.05]). CS (P<0.01) and HK (P<0.01) activities were lower in CHF patients than in HS, but PFK activity was higher (P<0.05). T(F) correlated significantly with CS (r=0.50), HADH (r=0.42), PFK (r=-0.47) and HK (r=0.41) activities and the PFK/CS ratio (r=-0.39) when both groups were considered, and with HADH (r=0.47) and PFK (r=-0.57) activities for the CHF group alone (all P<0.05). CONCLUSIONS: These results suggest that isometric endurance of the vastus lateralis muscle is reduced in patients with CHF and that it is related to a reduced muscle oxidative capacity.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

The muscle protein synthetic response to the combined ingestion of protein and carbohydrate is not impaired in healthy older men

Aging is associated with a progressive decline in skeletal muscle mass. It has been hypothesized that an attenuated muscle protein synthetic response to the main anabolic stimuli may contribute to the age-related loss of muscle tissue. The aim of the present study was to compare the muscle protein synthetic response following ingestion of a meal-like amount of dietary protein plus carbohydrate between healthy young and older men. Twelve young (21 ± 1 years) and 12 older (75 ± 1 years) men consumed 20 g of intrinsically l-[1-¹³C]phenylalanine-labeled protein with 40 g of carbohydrate. Ingestion of specifically produced intrinsically l-[1-¹³C]phenylalanine-labeled protein allowed us to assess the subsequent incorporation of casein-derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies obtained prior to and 2 and 6 h after protein plus carbohydrate ingestion. The acute post-prandial rise in plasma glucose and insulin concentrations was significantly greater in the older compared with the younger males. Plasma amino acid concentrations increased rapidly following drink ingestion in both groups. However, plasma leucine concentrations were significantly lower at t = 90 min in the older when compared with the young group (P < 0.05). Muscle protein-bound l-[1-¹³C]phenylalanine enrichments increased to 0.0071 ± 0.0016 and 0.0072 ± 0.0013 mole percent excess (MPE) at 2 h and 0.0229 ± 0.0016 and 0.0213 ± 0.0024 MPE at 6 h following ingestion of the intrinsically labeled protein in the young and older males, respectively, with no differences between groups (P > 0.05). We conclude that the use of dietary protein-derived amino acids for muscle protein synthesis is not impaired in healthy older men following intake of protein plus carbohydrate.     

Age-related atrophy of rat soleus muscle is accompanied by changes in fibre type composition,bioenergy decline and mtDNA rearrangements

A variety of techniques have been applied to investigate the interrelationship between age-related atrophy of rat soleus muscle and other signs of muscle aging, such as changes in muscle fibre type composition, decrease in bioenergy capacity and accumulation of mitochondrial DNA (mtDNA) arrangements. Age-related atrophy of rat soleus muscle was shown to start at the age of about28 months. It was accompanied by a decrease in the number of slow twitch muscle fibres (type I)and an increase in the proportion of muscle fibresco-expressing slow and fast myosins (type Ic and IIcfibres). Bioenergy capacity of the soleus muscle, assessed by the level of measurable cytochrome c oxidase (COX) activity, was found to be decreased both in the middle age and old rats compared to the young animals. Muscle atrophy was also accompanied by a decrease in the amount of full-length mitochondrial DNA (FL-mtDNA) amplifiable by the extra-long PCR (XL-PCR)and the increase in the number of mtDNA deletions. The results of the study show that the decline in the bioenergy capacity of the rat soleus occurs by the middle age. It is followed by the onset of the age-related muscle atrophy that is accompanied by both fibre type changes and functional mtDNA degradation. This revised version was published online in July 2006 with corrections to the Cover Date.     

Effect of recombinant human growth hormone on age-related hepatocyte changes in old male and female Wistar rats

Aging induces changes in several organs, such as the liver, and this process might be due to damage caused by free radicals and inflammatory mediators. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis shows a reduction with age, and this fact could be associated with some age-related changes. The aim of this study was to investigate the effect of GH administration on age-induced alterations in hepatocytes. Two and twenty two month-old male and female Wistar rats were used. Old rats were treated with human recombinant GH for 10 wk. At the end of the treatment, hepatocytes were isolated from the liver and cultured, and different parameters were measured in cells and medium. Plasma IGF-1 was also measured. Aging significantly decreased plasma IGF-1 in males. In females, plasma IGF-1 was also reduced, but not significantly. GH treatment restored plasma IGF-1 levels to values similar to young males. Aging was associated with a significant increase in lipid peroxidation (LPO), nitric oxide (NO), carbon monoxide (CO) and cyclic guanosyl-monophosphate (cGMP), as well as a reduction in adenosyl triphosphate (ATP) and phosphatidylcholine (PC) synthesis. GH administration partially prevented all these changes in males. In females, some of the parameters were significantly improved by GH (ATP, CO, cGMP), while others showed a tendency to improvement, although differences did not reach significance. In conclusion, GH administration could exert beneficial effects against age-related changes in hepatocytes, mainly in males.     

Skeletal muscle mass is a strong predictor of cardiorespiratory fitness in the Chinese population with obesity

Background and aimsAlthough skeletal muscle is well-known as physiologically related to VO₂max, the independent predictive value of skeletal muscle mass (SMM) VO₂max in people with obesity has not been studied. This study aims to determine the relationships between maximal oxygen uptake (VO₂max) and SMM in the Chinese population with obesity.Methods and resultsOverall, 409 participants with obesity were included in this cross-sectional study. A maximal and graded exercise testing measured VO₂max, and body compositions were measured by bioelectrical impedance analysis. Subsequently, correlation coefficients and stepwise multiple linear regression analyses were used to determine the relationships between VO₂max and body compositions. SMM was found to have a significant correlation with VO₂max (r = 0.290, P < 0.001) after adjusting for sex, age, body mass index (BMI), waist-to-hip ratio, and percent body fat (PBF). In previous studies, BMI was widely recognized as a strong predictor of VO₂max. This study revealed surprising results: after SMM was controlled, the correlation between BMI and VO₂max was reduced (from r = 0.381, P < 0.001 to r = 0.191, P < 0.001). SMM was found the most important independent predictor. In the regression model, the variance of VO₂max was explained by the SMM which accounted for 27.4%.ConclusionsIn summary, SMM is a stronger independent predictor of cardiorespiratory fitness in the Chinese population with obesity than sex, age, BMI, waist-to-hip ratio, and PBF.     

Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation

BACKGROUND: Patients with chronic heart failure demonstrate several skeletal muscle abnormalities. The underlying mechanisms are unclear. After cardiac transplantation, cardiac function is restored, but exercise capacity is still impaired. AIM: To evaluate the influence of cardiac transplantation on skeletal muscle fibre composition, fibre area and capillarization as well as muscle enzymes, lactate, thigh muscle area and strength. METHODS: Ten patients were longitudinally investigated before, 1-3 and 6-9 months after transplantation. Ten healthy individuals served as controls. A biopsy from the lateral vastus muscle was obtained and the thigh muscle area was measured with computed tomography. Muscle strength in the knee extensors and exercise capacity were also evaluated. RESULTS: Muscle lactate was elevated in patients vs. controls (3.6+/-3.0 vs. 1.5+/-0.7 mmol/kg wet wt., P=0.037), and decreased to normal (1.4+/-0.3 mmol/kg wet wt., P=0.038) after transplantation. Citrate synthase activity was decreased in patients (5.6+/-1.5 micromol/g wet wt./min) vs. controls (8.1+/-1.6 micromol/g wet wt./min, P=0.0018), and did not change post transplantation. Patients had decreased number of capillaries in contact with each fibre vs. controls (2.6+/-0.5 vs. 3.5+/-1.0, P=0.039) which persisted post transplantation. Exercise capacity increased after transplantation (74+/-22 vs. 118+/-26 W, P=0.0002), whereas muscle strength did not improve significantly. CONCLUSION: The persisting intrinsic abnormalities in skeletal muscle after cardiac transplantation may contribute to the impaired exercise capacity observed in cardiac transplant recipients.     

人生长激素拮抗剂对糖尿病小鼠肾病的干预作用

目的探讨人生长激素拮抗剂(GHA,又称生长激素受体拮抗剂)对糖尿病小鼠肾病的干预作用.方法雄性C57BL小鼠共39只,分为正常对照组、糖尿病(DM)对照组、GHA1组、GHA2组和人生长激素(hGH)组,链脲佐菌素诱发糖尿病,后三组分别注射GHA1、GHA2和人生长激素(hGH)为期11周.观察各组小鼠体重、肾脏形态和尿蛋白排泄情况.结果DM对照组、hGH组和二种GHA组小鼠体重增长差异无显著性.hGH组肾小球面积(4289±798)μm2和小球内细胞数(37.4±5.5)显著高于其他各组,二种GHA组肾小球面积和GHA2组小球内细胞数与正常对照组差异无显著性,各糖尿病组系膜区PAS阳性物质沉积差异无显著性.hGH和DM组尿蛋白排泄与GHA组相比差异无显著性.结论hGH可加重DM小鼠肾小球的肥大和小球内细胞增生,皮下注射GHA对预防糖尿病小鼠肾小球肥大、小球内细胞增殖及保持肾小球形态的完整性有一定作用.