5 Questions with Marcas Bamman, Ph.D. about response heterogeneity

Marcas Bamman, Ph.D.
Dr. Marcus Bamman, Professor, University of Alabama-Birmingham (UAB)

Interviewer: Mike Roberts, Ph.D.

Q1: Both of our laboratories have clearly observed that there are some folks that don’t “grow muscle” as well in response to resistance training.  Can you summarize the highlights of your research in this area?

This is a topic of great interest, and one that you and I share.  We call this phenomenon “inter-individual response heterogeneity,” which is actually applicable to any type of intervention and any given primary outcome. In our case, we’ve focused on resistance training-induced myofiber hypertrophy and/or whole muscle hypertrophy, but response heterogeneity exists across the board (e.g., individual responses to medications such as anti-hypertensives are highly heterogeneous).  Leveraging inter-individual differences in responsiveness opens the door to revealing any number of potential underlying mechanisms driving the intended outcome.

For resistance training-induced myofiber hypertrophy, we have found through a series of studies that there are major differences among untrained individuals “walking in the door” who eventually are identified as high vs. low responders after several weeks of intensive training, including differences at baseline in their muscle transcriptome profile and the number of available muscle stem cells. We also noted substantial differences in their initial molecular responses to the first full exercise bout, including the exercise-induced expression of pro-myogenic and pro-growth genes, and the induction of signaling processes that promote protein synthesis. Essentially, poor responders seem to be less responsive to each exercise bout at the molecular/signaling levels, or are perhaps “slow out of the gate.”  After weeks of training, we also noted major differences in the induction of ribosome biogenesis, presence of myogenic stem cells, and addition of myonuclei to myofibers.  In our view, these approaches are also valuable for ruling out potential mediators (e.g., we found no differences among response clusters in the ability to down-regulate myostatin expression, and we also noted several protein signaling responses that did not differ between response clusters).

We certainly have a great deal more to learn, in order to advance this intriguing scientific pursuit. We recently completed a dose-response resistance training trial, and another large-scale resistance training trial that both resulted in, as expected, substantial inter-individual response heterogeneity, and we are currently pursuing a number of novel directions including muscle RNAseq as well as miRNA profiling in muscle and in exosomes isolated from the circulation.  We suspect some of these miRNAs may be very important in conferring differences in post-transcriptional regulation among response clusters.

Q2: Contrary to question 1 above, one thing that both of our laboratories have observed is that both low and high responders do gain a substantial amount of strength in response to training. This is critical because it shows that one of the more adaptations persists in almost everyone.  What are your thoughts here?

This is an important point.  I want to emphasize that our pursuit of potential underpinnings for low vs. high responsiveness is based on a single primary outcome of interest.  This is by design. However, there are numerous positive responses experienced by essentially all study participants, including strength gains. For this reason, the idea of true “non-responders” is not supported (everyone we’ve tested responds positively on multiple outcomes, but not necessarily on the primary outcome of interest that underlies the cluster analysis). Because we typically study untrained participants, there are a number of non-muscle mass adaptations that promote gains in strength. Most of these tend to be based on an improved ability to activate motor units (more synchronous recruitment, frequency of firing, etc). Essentially, the untrained, naïve individual tends to rapidly improve strength simply by learning how to more fully activate their existing musculature.

In support of this concept, we noted in our first cluster analysis in 2007, that “non”-responders gained similar amounts of strength as the moderate and extreme responders over the first few weeks, but then plateaued in strength; whereas the two responder clusters continued to gain more strength during the latter weeks.  We attributed this phenomenon to the likely plateau in non-muscle mass-dependent strength gains; whereby continued strength gains in the latter weeks were more dependent on actual gains in myofiber size / muscle mass.

It is also worth noting that beyond strength gains, we have shown in all of these studies that the favorable IIx to IIa myofiber type shift occurs similarly in all participants, irrespective of whether they are a hypertrophy responder.  This is important for two reasons: (1) it is a valuable biomarker to ensure the training stimulus was sufficient in all participants to promote muscle tissue adaptations; and (2) it tells us that the mechanisms underlying myofiber hypertrophy are clearly distinct from those underlying the fiber type shift.

It is also important to point out that our response heterogeneity studies have all fallen in the category of “efficacy” or “per protocol” trials, meaning we have made every effort to control all potential mediators of adaptation (frequency, intensity, adherence, activities outside of supervised training) along with monitoring other potential mediators (e.g., medication usage, diet, sleep, etc).  This in our view is the most direct means of studying biological differences between response clusters.

Q3: You are heavily involved with the National Institute of Health’s MoTrPAC initiative, specifically the human clinical trial sites.  I know describing this in a paragraph may not be possible, but what is the overarching theme of this initiative?

MoTrPAC is a national, randomized controlled clinical trial (RCT) of resistance training vs. endurance training vs. no-exercise control, that is intended to reveal exercise-induced molecular transducers that potentially underlie known health benefits of endurance and/or resistance exercise training.  As you know, we lead one of the adult clinical centers for the consortium.  By performing acute exercise response studies with serial time course collections of blood, muscle, and adipose tissues – both before and after 12 weeks of supervised, progressive training – MoTrPAC will provide molecular maps (genetic/genomic, epigenomic, transcriptomic, proteomic, metabolomic, lipidomic) that will become publicly available and therefore benefit the entire scientific community toward advancing the field. In addition to the untrained, generally healthy men and women studied in the RCT, comparative studies in trained athletes, children, and rodents will add tremendous value.  

Q4: With regard to the MoTrPAC initiative, what will be some of the anticipated scientific breakthroughs in your opinion?

Among the novel information to be gained, certainly inter-individual response heterogeneity is of great interest, and MoTrPAC stands to advance this science in an unparalleled fashion (i.e. more than 2000 participants anticipated).  Producing the numerous molecular maps across these platforms, one can envision an incredibly rich dataset for future research. And because MoTrPAC will recruit generally healthy children and adults from age 11 to 60+ years, there will be opportunities to conduct parallel or subsequent ancillary studies in diseased cohorts that will further enhance the innovation and new knowledge gained.  For these studies, the “control” or “ideal” molecular responses and training adaptations will essentially be provided from the parent trial.  Overall, MoTrPAC is a huge opportunity for the field.

Q5: You are the Director of UAB’s Center for Exercise Medicine, which hosts an annual conference.  Can you highlight some of the Center’s efforts and tell our readers how to become more engaged?

Thank you for highlighting our Center.  Our vision for the UAB Center for Exercise Medicine (UCEM) is to foster an environment that establishes UAB among the nation’s leaders in exercise biology & medicine research & education. We foster research advances across 5 Pillars: (1) Precision (inter-individual response heterogeneity, dose-response optimization); (2) Regeneration (exercise-induced endogenous regenerative mechanisms); (3) Rehabilitation (acute and chronic disease, pre-surgery, post-surgery); (4) Interaction (exercise – drug/device interactions, multi-modal interventions); and (5) Sustainability (behavioral change, environmental factors).  Essentially our tagline – Moving Research into Medicine – is at the core of all programming in the Center.

The UCEM has over 200 UAB members across numerous disciplines and clinical sub-specialties, and several partnerships at collaborating institutions such as your outstanding group at Auburn U.  We host an annual symposium (each September) which continues to grow each year across the southeast region and beyond, and includes keynote lectures along with a travel award competition for pre- and post-doctoral trainees. The UCEM also hosts a monthly Distinguished Lecture Series, featuring prominent leaders in the field.  

In addition, we have an NIH-funded T32 training program for pre- and post-doctoral trainees that provides outstanding translational research training and career development. Potential trainees can learn more and apply via our website. Finally, the UCEM is home to the NIH National Rehabilitation Research Resource to Enhance Clinical Trials (REACT) and the Coordinating Center for the NIH Medical Rehabilitation Research Resource Network (MR3 Network).  These resource centers offer pilot study funding, study design and grant application consultations, access to core facilities, scholar awards, and other resources all intended to support the scientific community at several levels, and to ultimately advance the field. I certainly encourage investigators and trainees to leverage these resources, which again can be found on our websites for UCEM, REACT, or the MR3 Network.

Excellent. Thank you for your time today, Dr. Bamman!

Dr. Bamman is a Professor of Cell, Developmental and Integrative Biology as well as Medicine and Neurology, Director of the UAB Center for Exercise Medicine, and Director of the NIH National Rehabilitation Research Resource to Enhance Clinical Trials (REACT) at the University of Alabama at Birmingham School of Medicine. To find out more about Dr. Bamman and these research centers, check out:  www.uab.edu/exercise and www.react.center, and follow on Twitter @MarcasBamman and @UABExerciseMed.

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