Determinants of Skeletal Muscle Hypertrophy and the Attenuated Hypertrophic Response at Old Age

In 2012 we will again see the impressive achievements of many athletes during the London Olympic Games. In particular for weightlifters success is dependent on the power- and force-generating capacity of their muscles, which in turn are strongly determined by muscle mass. Many athletes and bodybuilders therefore train intensively to develop as much muscle hypertrophy as possible. Unlimited hypertrophy, however, is impossible. Limitations may be imposed by the peak forces that the tendons, bones and joints can cope with, but also by factors within the muscles themselves. For instance, an increase in pennation angle, which accompanies hypertrophy, beyond 450 would result in a reduction in muscle strength even if muscle mass continuous to increase. There also is a trade-off between metabolism and diffusion, where highly oxidative fibers require shorter diffusion distances, and hence smaller fibers, for adequate oxygen supply to the mitochondria, than glycolytic fibers. A similar situation applies to the myonuclei where transcripts are distributed over the cell mainly by diffusion and unbridled hypertrophy would, at least in theory, cause serious problems with fiber maintenance. Despite these limiting factors muscles in bodybuilders can be as much as 74% larger than in the normal population. Elderly people have a lower muscle mass that may cause problems with daily life activities and an increase in muscle strength would improve their quality of life. There are indications, however, that the maximal attainable hypertrophy is significantly reduced in the elderly. Here it is suggested that while individual fibers in the elderly may hypertrophy to a similar extent as their younger counterparts, the age-related loss of muscle fibers is an additional limiting factor of the whole muscle hypertrophy at old age

Comparison of MRI and DXA to measure muscle size and age-related atrophy in thigh muscles.

OBJECTIVES Magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) were used to examine the thigh lean mass in young and old men and women. METHODS A whole-body DXA scan was used to estimate thigh lean mass in young (20 men; 22.4±3.1y; 18 women; 22.1±2.0y) and older adults (25 men; 72.3±4.9y; 28 women; 72.0±4.5y). Thigh lean mass determined with a thigh scan on the DXA or full thigh MRI scans were compared. RESULTS Although the thigh lean mass quantified by DXA and MRI in young and older participants were correlated (R(2)=0.88; p<0.001) the magnitude of the differences in thigh lean mass between young and old was smaller with DXA than MRI (old vs. young men 79.5±13.1% and 73.4±11.2%; old vs. young women 88.6±11.8% and 79.4±12.3%, respectively). Detailed analysis of MRI revealed 30% smaller quadriceps muscles in the older than young individuals, while the other thigh muscles were only 18% smaller. CONCLUSIONS DXA underestimates the age-related loss of thigh muscle mass in comparison to MRI. The quadriceps muscles were more susceptible to age-related atrophy compared with other thigh muscles

Do PTK2 gene polymorphisms contribute to the interindividual variability in muscle strength and the response to resistance training? A preliminary report.

The protein tyrosine kinase-2 (PTK2) gene encodes focal adhesion kinase, a structural protein involved in lateral transmission of muscle fiber force. We investigated whether single-nucleotide polymorphisms (SNPs) of the PTK2 gene were associated with various indexes of human skeletal muscle strength and the interindividual variability in the strength responses to resistance training. We determined unilateral knee extension single repetition maximum (1-RM), maximum isometric voluntary contraction (MVC) knee joint torque, and quadriceps femoris muscle specific force (maximum force per unit physiological cross-sectional area) before and after 9 wk of knee extension resistance training in 51 untrained young men. All participants were genotyped for the PTK2 intronic rs7843014 A/C and 3'-untranslated region (UTR) rs7460 A/T SNPs. There were no genotype associations with baseline measures or posttraining changes in 1-RM or MVC. Although the training-induced increase in specific force was similar for all PTK2 genotypes, baseline specific force was higher in PTK2 rs7843014 AA and rs7460 TT homozygotes than in the respective rs7843014 C- (P = 0.016) and rs7460 A-allele (P = 0.009) carriers. These associations between muscle specific force and PTK2 SNPs suggest that interindividual differences exist in the way force is transmitted from the muscle fibers to the tendon. Therefore, our results demonstrate for the first time the impact of genetic variation on the intrinsic strength of human skeletal muscle

The Evolutionary Dynamics of Digital and Nucleotide Codes: A Mutation Protection Perspective

Both digital codes in computers and nucleotide codes in cells are protected against mutations. Here we explore how mutation protection affects the random change and selection of digital and nucleotide codes. We illustrate our findings with a computer simulation of the evolution of a population of self replicating digital amoebae. We show that evolutionary programming of digital codes is a valid model for the evolution of nucleotide codes by random change within the boundaries of mutation protection, not for evolution by unbounded random change. Our mutation protection perspective enhances the understanding of the evolutionary dynamics of digital and nucleotide codes and its limitations, and reveals a paradox between the necessity of dysfunctioning mutation protection for evolution and its disadvantage for survival. Our mutation protection perspective suggests new directions for research into mutational robustness

Are Force Enhancement after Stretch and Muscle Fatigue Due to Effects of Elevated Inorganic Phosphate and Low Calcium on Cross Bridge Kinetics?

Background andObjectives: Muscle fatigue is characterised by (1) loss of force, (2) decreased maximal shortening velocity and (3) a greater resistance to stretch that could be due to reduced intracellular Ca2+ and increased Pi, which alter cross bridge kinetics. Materials and Methods: To investigate this, we used (1) 2,3-butanedione monoxime (BDM), believed to increase the proportion of attached but non-force-generating cross bridges; (2) Pi that increases the proportion of attached cross bridges, but with Pi still attached; and (3) reduced activating Ca2+. We used permeabilised rat soleus fibres, activated with pCa 4.5 at 15 °C. Results: The addition of 1 mM BDM or 15 mM Pi, or the lowering of the Ca2+ to pCa 5.5, all reduced the isometric force by around 50%. Stiffness decreased in proportion to isometric force when the fibres were activated at pCa 5.5, but was well maintained in the presence of Pi and BDM. Force enhancement after a stretch increased with the length of stretch and Pi, suggesting a role for titin. Maximum shortening velocity was reduced by about 50% in the presence of BDM and pCa 5.5, but was slightly increased by Pi. Neither decreasing Ca2+ nor increasing Pi alone mimicked the effects of fatigue on muscle contractile characteristics entirely. Only BDM elicited a decrease of force and slowing with maintained stiffness, similar to the situation in fatigued muscle. Conclusions: This suggests that in fatigue, there is an accumulation of attached but low-force cross bridges that cannot be the result of the combined action of reduced Ca2+ or increased Pi alone, but is probably due to a combination of factors that change during fatigue

The impact of resveratrol and hydrogen peroxide on muscle cell plasticity shows a dose-dependent interaction

While reactive oxygen species (ROS) play a role in muscle repair, excessive amounts of ROS for extended periods may lead to oxidative stress. Antioxidants, as resveratrol (RS), may reduce oxidative stress, restore mitochondrial function and promote myogenesis and hypertrophy. However, RS dose-effectiveness for muscle plasticity is unclear. Therefore, we investigated RS dose-response on C2C12 myoblast and myotube plasticity 1. in the presence and 2. absence of different degrees of oxidative stress. Low RS concentration (10 μM) stimulated myoblast cell cycle arrest, migration and sprouting, which were inhibited by higher doses (40–60 μM). RS did not increase oxidative capacity. In contrast, RS induced mitochondria loss, reduced cell viability and ROS production, and activated stress response pathways [Hsp70 and pSer36-p66(ShcA) proteins]. However, the deleterious effects of H2O2 (1000 µM) on cell migration were alleviated after preconditioning with 10 µM-RS. This dose also enhanced cell motility mediated by 100 µM-H2O2, while higher RS-doses augmented the H2O2-induced impaired myoblast regeneration and mitochondrial dehydrogenase activity. In conclusion, low resveratrol doses promoted in vitro muscle regeneration and attenuated the impact of ROS, while high doses augmented the reduced plasticity and metabolism induced by oxidative stress. Thus, the effects of resveratrol depend on its dose and degree of oxidative stress

Muscle Growth, Repair and Preservation: A Mechanistic Approach

Resistance exercise, amino acid ingestion and an anabolic hormone environment all have the capacity to elevate muscle protein synthesis (MPS), while a catabolic hormone environment, such as elevated pro-inflammatory cytokines as seen during disuse, aging, and conditions such as cancer and AIDS, can cause an increase in muscle protein degradation (MPD). When the rate of MPS exceeds that of MPD there is a positive net protein balance (NPB) and over a prolonged period of time this results in accretion of contractile material and muscle growth, or hypertrophy. In contrast, when NPB is chronically negative, muscle atrophy occurs, i.e. muscle size decreases. Various signaling pathways within the muscle fiber appear to play a crucial role in the adaptive processes, and understanding how these pathways can be modulated will help the design of therapies to prevent or reverse muscle atrophy in a host of muscle wasting conditions