Impact of β-hydroxy β-methylbutyrate (HMB) on age-related functional deficits in mice

The impact of mechanically stimulated muscle-derived stromal cells on aged skeletal muscle

“…Based on the results, we speculated that mechanical strain preconditioning of mMSCs prior to transplantation could potentially promote the release of regenerative factors necessary to initiate adaptation in aged skeletal muscle in the absence of exercise, including progenitor cell activation and myofiber growth. In addition, consistent with 1) recent studies that suggest a role for systemic factors in exercisemediated neuroplasticity [Gu et al, 2012;Moon et al, 2016;Wrann et al, 2013] and 2) evidence of a decline in mMSC neurogenic factor secretion (BDNF, NGF, FNDC5) in aged muscle [Munroe et al, 2017], we secondarily hypothesized that intramuscular transplantation of preconditioned mMSCs could confer beneficial outcomes in the distal central nervous system.…”

“…2F-G). We previously reported small, but significant reductions in gastrocnemius-soleus complex weight (175--200 mg vs. 225--250 mg absolute weight) and strength in strain-matched aged mice compared to young [Munroe et al, 2017]. The lack of significant increase in muscle structure or function with a single injection in the current study suggests one of the following: 1) mechanical strain is not the biophysical cue required for mMSC-mediated promotion of adaptation following exercise training observed in young mice [Zou et al, 2015], 2) exogenously administered mMSCs cannot overcome significant fibrosis and declines in structure and function associated with advanced muscle aging (irreversible damage), and/or 3) higher doses of preconditioned mMSCs or multiple rounds of injection are required to overcome barriers and effectively rejuvenate aged muscle.…”

“…The success of the in vitro experiments encouraged us to evaluate the extent to which preconditioned mMSCs could improve the structure and function of aged skeletal muscle. We chose to target aged animals only, and not young mice, due to the significant deficit in mMSC function previously observed in aged mice [Munroe et al, 2017]. No changes were observed in muscle weight or fiber size in aged mice at 1 or 4 wks following injection.…”

“…Perivascular stromal cells, including mMSCs, may also underlie anabolic resistance in the context of aging. We recently isolated and evaluated perivascular stromal cell function in sedentary (non-exercised) aged mice compared to young adult controls [Munroe et al, 2017]. The results from this study demonstrated that mMSC gene expression is robustly compromised in aged muscle, as evidenced by reduced transcription of several regenerative growth [epidermal growth factor (EGF), leukemia inhibitory factor (LIF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor alpha (VEGFα)], neurotrophic [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), fibronectin type II domain 5 (Fndc5)], and ECM remodeling proteins [matrix metalloproteinases 2 and 14 (MMP2/14), collagen 1α1] that are collectively important for muscle repair and remodeling.…”

“…Tumor necrosis alpha (TNFα) gene expression was also elevated in aged mMSCs compared to young. The aged mMSC transcriptional signature suggests that aberrant stromal cell function may contribute to anabolic resistance and the subsequent loss of muscle structure and function during the natural process of aging [Munroe et al, 2017]. This information, as well as the unique immune-privileged status of MSCs [Meirelles Lda et al, 2009;Ranganath et al, 2012] and limitations associated with satellite cell transplantation, justify the development of mMSC-focused strategies for the prevention and treatment of age-related disability.…”