Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation

Age-related skeletal muscle sarcopenia is linked with increases in falls, fractures, and death and therefore has important socioeconomic consequences. The molecular mechanisms controlling age-related muscle loss in humans are not well understood, but are likely to involve multiple signaling pathways. This study investigated the regulation of several genes and proteins involved in the activation of key signaling pathways promoting muscle hypertrophy, including GH/STAT5, IGF-1/Akt/GSK-3β/4E-BP1, and muscle atrophy, including TNFα/SOCS-3 and Akt/FKHR/atrogene, in muscle biopsies from 13 young (20 ± 0.2 years) and 16 older (70 ± 0.3 years) males. In the older males compared to the young subjects, muscle fiber cross-sectional area was reduced by 40–45% in the type II muscle fibers. TNFα and SOCS-3 were increased by 2.8 and 1.5 fold, respectively. Growth hormone receptor protein (GHR) and IGF-1 mRNA were decreased by 45%. Total Akt, but not phosphorylated Akt, was increased by 2.5 fold, which corresponded to a 30% reduction in the efficiency of Akt phosphorylation in the older subjects. Phosphorylated and total GSK-3β were increased by 1.5 and 1.8 fold, respectively, while 4E-BP1 levels were not changed. Nuclear FKHR and FKHRL1 were decreased by 73 and 50%, respectively, with no changes in their atrophy target genes, atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated by 2 and 1.4 fold. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signaling proteins such as GHR, IGF-1, and Akt. TNFα, SOCS-3, and myostatin are potential candidates influencing this anabolic perturbation.

Associations between sedentary behaviour and body composition, muscle function and sarcopenia in community-dwelling older adults

Summary: While previous studies have reported detrimental associations of sedentary behaviours with cardiometabolic disorders and mortality, in this study, we report that higher levels of sitting time were associated with a greater risk of sarcopenia, with increased television (TV) viewing negatively associated with lean mass, independent of physical activity.

Fall and fracture risk in sarcopenia and dynapenia with and without obesity: the role of lifestyle interventions

Due to their differing etiologies and consequences, it has been proposed that the term "sarcopenia" should revert to its original definition of age-related muscle mass declines, with a separate term, "dynapenia", describing muscle strength and function declines. There is increasing interest in the interactions of sarcopenia and dynapenia with obesity. Despite an apparent protective effect of obesity on fracture, increased adiposity may compromise bone health, and the presence of sarcopenia and/or dynapenia ("sarcopenic obesity" and "dynapenic obesity") may exacerbate the risk of falls and fracture in obese older adults. Weight loss interventions are likely to be beneficial for older adults with sarcopenic and dynapenic obesity but may result in further reductions in muscle and bone health. The addition of exercise including progressive resistance training and nutritional strategies, including protein and vitamin D supplementation, may optimise body composition and muscle function outcomes thereby reducing falls and fracture risk in this population.

Sarcopenia and the common mental disorders: a potential regulatory role of skeletal muscle on brain function?

While it is understood that body composition impacts on physical conditions, such as diabetes and cardiovascular disease, it is only now apparent that body composition might play a role in the genesis of common mental disorders, depression and anxiety. Sarcopenia occurs in ageing and comprises a progressive decline in muscle mass, strength and function, leading to frailty, decreased independence and poorer quality of life. This review presents an emerging body of evidence to support the hypothesis that shared pathophysiological pathways for sarcopenia and the common mental disorders constitute links between skeletal muscle and brain function. Contracting skeletal muscle secretes neurotrophic factors that are known to play a role in mood and anxiety, and have the dual role of nourishing neuronal growth and differentiation, while protecting the size and number of motor units in skeletal muscle. Furthermore, skeletal muscle activity has important immune and redox effects that impact behaviour and reduce muscle catabolism.

Low lean tissue mass and physical performance as markers of sarcopenia in older men and women

Background: While declines in muscle mass and function occur in all individuals with advancing age, the extent and rate of decline vary in the general population. We aimed to determine the prevalence of low lean tissue mass combined with poor physical function as an indicator of sarcopenia among older men and women residing in southeastern Australia.

Methods: The study involved men and women aged 60+ years from the Geelong Osteoporosis Study (GOS). Skeletal muscle mass was measured as total lean tissue mass by dual energy x-ray absorptiometry (DXA) and expressed as a percentage of body weight to generate the skeletal mass index (SMI); low lean mass was defined as SMI T-score <-1. Low muscle function was based on performance using “timed up-and-go” scores >10s. Physical activity scores were determined using a validated questionnaire for the elderly and falls were self-reported for the previous year. Associations between sarcopenia, physical activity and falls were determined using multivariable regression techniques.

Results: Among 624 men, 233 had low SMI, 169 had low muscle performance and 81 had both, thus meeting criteria for sarcopenia. Among 436 women, 143 had low SMI, 179 had low muscle performance and 70 had both. A general age-related increase in the observed prevalence of sarcopenia appeared to be driven by an age-related increase in low performance. Sarcopenia was associated with lower physical activity scores. No association was detected between sarcopenia and falls for men but an association was observed for women (age-adjusted OR 1.87, 95% CI 1.11, 3.14).

Conclusion: In our population, the prevalence of sarcopenia was 10.6% (95% CI 7.7, 13.4) for men and 14.5% (95% CI 10.8, 18.3) for women. Men and women with sarcopenia were habitually less active and, for women, sarcopenia was associated with increased likelihood of falls.

Hypertrophic signalling in human skeletal muscle

Ý-lactoglobulin enriched whey protein isolate, but not carbohydrate, increased growth signalling in human skeletal muscle when consumed in conjunction with resistance exercise. Ageing did not impair the anabolic signalling response; however this response was attenuated after training. These findings help identify strategies to prevent, or delay the onset of sarcopenia.

Independent and combined effects of exercise and vitamin D on muscle morphology, function and falls in the elderly

Regular exercise, particularly progressive resistance training (PRT), is recognized as one of the most effective strategies to prevent age-related muscle loss (sarcopenia), but its effects on muscle function are mixed. However, emerging data indicates that high velocity PRT (fast concentric muscle contractions) is more effective for improving functional outcomes than traditional PRT. In terms of falls prevention, high-challenging balance training programs appear to be most effective. There is also compelling evidence that supplemental vitamin D is an effective therapeutic option for falls prevention. The findings from a recent meta-analysis revealed that supplemental vitamin D at a dose of at least 700–1,000 IU/d or an achieved serum 25(OH)D level of at least 60 nmol/L was associated with reduced falls risk among older individuals. Based on these findings, it is possible that the combination of exercise and vitamin D could have a synergistic effect on muscle morphology and function, particularly since both interventions have been shown to have beneficial effects on type II “fast twitch” muscle fibers and systemic inflammation, which have both been linked to losses in muscle mass and function. Unfortunately however, the findings from the limited number of factorial 2 × 2 design RCTs indicate that additional vitamin D does not enhance the effects of exercise on measures of muscle morphology, function or falls risk. However, none of these trials were adequately powered to detect a “synergistic” effect between the two treatment strategies, but it is likely that if an exercise-by-vitamin D interaction does exist, it may be limited to situations when vitamin D deficiency/insufficiency is corrected. Further targeted research in “high risk” groups is still needed to address this question, and evaluate whether there is a threshold level of serum 25(OH)D to maximize the effects of exercise on muscle and falls risk.

Aging and its effects on inflammation in skeletal muscle at rest and following exercise-induced muscle injury

The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Counteracting the progressive loss of muscle mass that occurs in the elderly, known as sarcopenia, represents a major hurdle in achieving these goals. Indirect evidence for a role of inflammation in sarcopenia is that markers of systemic inflammation correlate with the loss of muscle mass and strength in the elderly. More direct evidence is that compared with skeletal muscle of young people, the number of macrophages is lower, the gene expression of several cytokines is higher, and stress signaling proteins are activated in skeletal muscle of elderly people at rest. Sarcopenia may also result from inadequate repair and chronic maladaptation following muscle injury in the elderly. Macrophage infiltration and the gene expression of certain cytokines are reduced in skeletal muscle of elderly people compared with young people following exercise-induced muscle injury. Further research is required to identify the cause(s) of inflammation in skeletal muscle of elderly people. Additional work is also needed to expand our understanding of the cells, proteins, and transcription factors that regulate inflammation in the skeletal muscle of elderly people at rest and after exercise. This knowledge is critical for devising strategies to restrict sarcopenia, and improve the health of today's elderly population.

Musculoskeletal deterioration in men accompanies increases in body fat

Objective
To examine body fat and musculoskeletal changes in men over 5 years.

Methods
Body composition was evaluated for men in the Geelong Osteoporosis Study using whole body dual energy X-ray absorptiometry (DXA) during two time-periods. DXA was performed for 1329 men (25-96 years) during 2001-2006 and for 900 men (25-98 years), 2006-2011. The masses of fat, lean, and bone were expressed relative to the square of height (kg/m2). Each compartment was also expressed as a percentage relative to body weight (%fat, %lean, %bone).

Results
Mean BMI increased from 26.9 kg/m2 in 2001-2006, to 27.2 kg/m2 in 2006-2011 (P = 0.04). Mean fat mass increased by 9.0% from 6.98 kg/m2 (95%CI 6.84-7.11) in 2001-2006, to 7.60 kg/m2 (7.44-7.77) in 2006-2011 (P < 0.001); mean lean mass decreased by 0.9%, from 18.92 kg/m2 (18.83-19.01) to 18.75 kg/m2 (18.64-18.86) (P = 0.02), and mean bone mass decreased 1.6% from 1.041 kg/m2 (1.034-1.047), to 1.024 kg/m2 (1.016-1.032). Mean %fat increased from 23.4% to 25.2%, mean %lean decreased from 72.6% to 70.9% and mean %bone decreased from 4.0% to 3.9% (all P < 0.05).

Conclusions
An increase in BMI, which reflects a substantial increase in body fat mass and declines in both lean and bone mass was reported. This may have implications for future development of bone fragility, sarcopenia, and sarcopenic obesity.

Versican processing by a disintegrin-like and metalloproteinase domain with thrombospondin-1 repeats proteinases-5 and -15 facilitates myoblast fusion

Skeletal muscle development and regeneration requires the fusion of myoblasts into multinucleated myotubes. Because the enzymatic proteolysis of a hyaluronan and versican-rich matrix by ADAMTS versicanases is required for developmental morphogenesis, we hypothesized that the clearance of versican may facilitate the fusion of myoblasts during myogenesis. Here, we used transgenic mice and an in vitro model of myoblast fusion, C2C12 cells, to determine a potential role for ADAMTS versicanases. Versican processing was observed during in vivo myogenesis at the time when myoblasts were fusing to form multinucleated myotubes. Relevant ADAMTS genes, chief among them Adamts5 and Adamts15, were expressed both in developing embryonic muscle and differentiating C2C12 cells. Reducing the levels of Adamts5 mRNA in vitro impaired myoblast fusion, which could be rescued with catalytically active but not the inactive forms of ADAMTS5 or ADAMTS15. The addition of inactive ADAMTS5, ADAMTS15, or full-length V1 versican effectively impaired myoblast fusion. Finally, the expansion of a hyaluronan and versican-rich matrix was observed upon reducing the levels of Adamts5 mRNA in myoblasts. These data indicate that these ADAMTS proteinases contribute to the formation of multinucleated myotubes such as is necessary for both skeletal muscle development and during regeneration, by remodeling a versican-rich pericellular matrix of myoblasts. Our study identifies a possible pathway to target for the improvement of myogenesis in a plethora of diseases including cancer cachexia, sarcopenia, and muscular dystrophy.

Total and Appendicular Lean Mass Reference Ranges for Australian Men and Women: The Geelong Osteoporosis Study

The aim of this study was to develop reference ranges for total and appendicular lean mass measured using dual-energy X-ray absorptiometry (DXA) from a randomly selected population-based sample of men and women residing in southeastern Australia. Men (n = 1,411) and women (n = 960) aged 20–93 years, enrolled in the Geelong Osteoporosis Study, were randomly selected from the Barwon Statistical Division using the electoral roll as a sampling frame in 2001–2006 (67 % participation) and 1993–1997 (77 % participation), respectively. Using DXA (Lunar DPX-L or Prodigy Pro) at baseline for men and at the 10-year follow-up for women (2004–2008), total and appendicular lean mass were measured. Means and standard deviations for each lean mass measure (absolute and relative to height squared) were generated for each age decade, and cutpoints equivalent to T scores of −2.0 and −1.0 were calculated using data from young adult men and women aged 20–39 years. Young adult reference data were derived from 374 men and 308 women. Cutpoints for relative appendicular lean mass equal to T scores of −2.0 and −1.0 were 6.94 and 7.87 kg/m2 for men and 5.30 and 6.07 kg/m2 for women. The proportions of men and women aged ≥80 years with a T score less than −2.0 were 16.0 and 6.2 %, respectively. These reference ranges may be useful for identifying lean mass deficits in the assessment of muscle wasting and sarcopenia.