One of the hallmarks of exercise training is the remodeling of skeletal muscle that can occur. Perhaps the most notable example of such adaptation is the hypertrophy of skeletal muscle associated with strength training. Additionally, with de-training, immobilization, and other forms of reduced use, there can also be significant skeletal muscle atrophy. In the last 10 or 20 yrs, significant progress has been made in understanding the molecular mechanisms that contribute to these responses. This progress is also generating insight into how aging skeletal muscle adapts to use and disuse, and into the effect of specific modes of contraction on the skeletal muscle adaptations to “resistance” exercise. In this general context it appears as if activation of specific cellular pathways in conjunction with insulin are the keys to skeletal muscle hypertrophy. In an outstanding review article, Kimball, Farrell and Jefferson (1) summarize the intracellular mechanisms associated with changes in protein synthesis in skeletal muscles. They highlight emerging information from a variety of sources and emphasize basic information coming from rodent models. Whenever possible, this information is integrated with data from human studies. These authors demonstrate how a combination of insulin and increased amino acid availability in conjunction with exercise can stimulate translation of messenger RNA and the initiation of protein synthesis. They highlight the activation of the ribosomal protein S6 protein kinase (S6K1) as well as the role of eukaryotic initiation factors (eIF4G and eIF4E). A key idea in both the protein synthetic responses to endurance exercise and strength training is that a small amount of insulin is required. The overall goal of the review is to summarize and integrate a number of studies on the interactions of insulin, amino acids, and exercise as they regulate protein synthesis in skeletal muscle.
The strengths of this manuscript include its clear review of the basic biochemical and molecular pathways involved in skeletal muscle protein synthesis: how these pathways are regulated, how they interact with various forms of exercise, and how insulin plays a key role in this entire response. Many of the ideas put forth in this study will stimulate human studies on related topics. Some of the studies are likely to be quite mechanistic; others might be applied, and rely on creative training interventions, measurements of muscle function, and body composition in selected populations.
In another paper, Adams, Cheng, Haddad and Baldwin (2) compare the effects of isometric exercise and muscle shortening and lengthening contractions on activation of intercellular pathways associated with skeletal muscle hypertrophy. These authors used a rat model of electrically stimulated contractions that included 10 training sessions over 20 d. The stimulation parameters they chose kept the duration of stimulation similar across the three modes. While the authors kept the duty cycles of contractions similar, the torque integral was greatest for the lengthening contractions, and least for the shortening contractions. Muscle mass increased 14% with the isometric contractions, 12% with the shortening contractions, and 11% with the lengthening contractions. Interestingly, while all three modes of training caused similar increases in total muscle DNA and RNA, only isometric and shortening contractions increased the levels of muscle insulin-like growth factor 1 (IGF1) mRNA. Changes in the insulin-signaling pathway were less dramatic with lengthening contractions. The authors conclude that “these results indicate that relatively pure movement mode exercises result in similar levels of compensatory hypertrophy that do not necessarily track with the total amount of force generated during contractions.” Additionally, the absence and increase in IGF-1 mRNA levels with lengthening contractions suggest that follow-up studies with other models (especially human) should be conducted. This is especially important because of the re-emerging interest in incorporating lengthening contractions into strength training programs in humans. The observations from this study also support previous studies demonstrating how measures of “work” performed during strength training may not be directly correlated with the magnitude of the adaptive response in the skeletal muscle.
In a third paper Morris, Spangenburg, and Booth (3) examined how skeletal muscle recovers from disuse caused by immobilization, and determined whether or not the intercellular pathways associated with this response and the response itself differ in young and older rodent skeletal muscles. The main findings of this study were that 10 d of immobilization (casting) caused about a 20% reduction in soleus muscle weight in older animals. This was about 50% less than atrophy seen in younger animals. By contrast, there was little or no regrowth of the soleus muscle after the immobilization was stopped; this was consistent with a number of studies using much longer duration immobilization protocols. It is also consistent with previous studies demonstrating that the ability of older skeletal muscle to undergo compensatory hypertrophy was blunted or absent in aging animals. Associated with these findings on muscle atrophy and the absence of regrowth, specific defects were seen in cell signaling pathways during recovery in older versus younger animals. The main finding is that there was a delayed activation of several of the specific signaling pathways discussed earlier, and that this may limit recovery with aging. Studies on these pathways can now be targeted to determine the key site of defective recovery from immobilization in older animals. When the defective pathways are better understood, perhaps training, dietary, or pharmacologic strategies could be used to reactivate them. Understanding why old muscle fails to regrow after immobilization could have great consequences for rehabilitation medicine and integrative studies of aging humans.
Great progress has been made in understanding the intercellular pathways associated with how muscles gain, lose, and regain mass. It is tempting to speculate that these molecular findings will serve as a basis for future intervention studies in humans, and they may have a special relevance to exercise training and rehabilitation in older subjects.
1. Kimball, S.R., P.A. Farrell, L.S. Jefferson. Role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. J. Appl. Physiol.
2. Adams, G.R., D.C. Cheng, F. Haddad, K.M. Baldwin. Skeletal muscle hypertrophy in response to isometric, lengthening, and shortening training bouts of equivalent duration. J. Appl. Physiol.
3. Morris, R.T., E.E. Spangenburg, F.W. Booth. Responsiveness of cell signaling pathways during the failed 15-d regrowth of aged skeletal muscle. J. Appl. Physiol.